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Relationship of Urinary Myelin Basic Protein–Like Material With Cranial Magnetic Resonance Imaging in Advanced Multiple Sclerosis
John N. Whitaker, MD;
Jerry S. Wolinsky, MD;
Ponnada A. Narayana, PhD;
Alfred A. Bartolucci, PhD;
John H. Noseworthy, MD;
Fred D. Lublin, MD;
Anders Linde, MB;
Per Gjörstrup, MD, PhD;
Herman C. Sullivan, MD;
for the North American Linomide Investigators
Arch Neurol. 2001;58:49-54.
ABSTRACT
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Background A significant correlation exists between disability and the volume of
black holes (BHL VOL), defined as hypointense lesions on T1-weighted cranial
magnetic resonance imaging. A consistent correlation has also been reported
between urinary myelin basic protein–like material (MBPLM) and the transition
toward secondary progression (SP) from relapsing-remitting (RR) multiple sclerosis
(MS).
Objective To improve the management of MS through a noninvasive and cost-effective
test for monitoring disease activity or disease status.
Design and Methods From 662 patients with MS (86 with RR MS, 259 with SP MS without continued
attacks, and 317 with SP MS with continued attacks), 24-hour urine samples
were obtained at enrollment in the phase 3 Linomide (roquinimex) drug study.
The urine specimens were analyzed for MBPLM and correlated with clinical features
and findings on cranial magnetic resonance imaging.
Results Significant but weak correlations existed between urinary MBPLM and
BHL VOL in all patients with MS (r = 0.114, P = .003; n = 662), patients with SP MS without attacks
(r = 0.185, P = .003; n
= 259), and all patients with SP MS (r = 0.122, P = .003; n = 576). No significant correlations were detected
in the RR MS group or any of the disease groups or subgroups whose Expanded
Disability Status Scale score was 5.0 or lower. In subgroup analysis, the
most significant correlation was detected between urinary MBPLM after adjustment
for creatinine and BHL VOL in patients with SP MS with an Expanded Disability
Status Scale score of 5.5 or higher but without continued relapses (r = 0.417, P<.001; n = 138).
Conclusions In patients with advanced SP MS, urinary MBPLM may possibly serve as
an indicator of failed remission and axonal damage. Urinary MBPLM correlates
with disease status in MS, especially the transition of RR MS to SP MS with
advancing disability.
INTRODUCTION
MANY IMPORTANT advances have been made in recent years in the clinical
management of patients with multiple sclerosis (MS). Among those are the increased
accuracy and certainty of diagnosis,1, 2
recognition of clinical subtypes,3 and the
introduction of 2 types of immunomodulatory agents, type 1 interferons and
glatiramer acetate, which have been shown to improve the natural history of
MS by reducing the number of relapses4, 5, 6
and slowing progression6 of relapsing-remitting
(RR) MS and slowing progression of secondary progressive (SP) MS.7 Numerous trials with a number of agents are now in
progress or being planned. This new stage in managing MS has increased the
awareness of the need to be able to conduct clinical trials more rapidly and
reliably and to monitor patients with MS to determine treatment failure. The
latter is particularly important, since RR MS changes to SP MS and the patient
becomes increasingly disabled.
A surrogate marker is defined as a nonclinical assessment that may predict
ultimate clinical change.8 Among the various
procedures that might be used as such a marker in MS, cranial magnetic resonance
imaging (MRI) has been firmly established as a noninvasive means to aid in
the diagnosis and gauge the dynamic changes occurring in MS.9
Although gadolinium-enhancing T1 lesions on cranial MRI imply active phases
with disruption of the blood-brain barrier with perivenular inflammatory collections,10 correlations with progression of disease have been
more difficult to ascertain. For example, spatial mapping of T2 and gadolinium-enhancing
T1 lesion volumes does not appear directly linked and suggests that progressive
gliosis and wallerian degeneration may occur without an inflammatory disruption
of the blood-brain barrier.11 Attempts to measure
a variety of changes on cranial MRI and loss of central nervous system tissue
volume accompanying atrophy are addressing the onset and progression of disability
in MS.12, 13 The presence of decreased
signals, commonly referred to as black holes,14
on T1-weighted images and cervical spinal cord atrophy in the upper segments15 appear to be the best neuroimaging correlates of
disability, and inferentially progression, of MS. Diminished N-acetylaspartate detected by magnetic resonance spectroscopy relates
directly to disease disability and progression16, 17, 18
and correlates with the severity of the hypointense T1 lesions.19, 20
Urinary myelin basic protein–like material (MBPLM) also correlates
with disease progression.21, 22, 23, 24
Urinary MBPLM has been used to designate an immunoreactive substance(s) detected
by antibodies reactive with MBP. The major chemical component of urinary MBPLM
has recently been identified as p-cresol sulfate.25
It is known that MBPLM in urine represents material that (1) cross-reacts
with a cryptic epitope in MBP peptide 83-8922;
(2) is normally present in low levels in neonates that rise above adult levels
in childhood26; (3) is normal in RR MS but
elevated in SP MS and, to a lesser degree, in primary progressive MS23, 27; (4) does not correlate with disease
activity in MS22; (5) when elevated, correlates
with a transition to the SP phase of MS from RR MS23, 24;
and (6) when elevated, correlates with lesion number and volume of T2-weighted
central nervous system lesions manually identified and quantitated on 0.15-T
cranial MRI.23
The predictive value of the level of urinary MBPLM in a large prospective
trial was planned as an "add-on" study in the multicenter Linomide (roquinimex)
trial on RR and SP MS.28 In this article, the
results at enrollment of that investigation are described with evidence presented
to demonstrate that urinary MBPLM, alone or after adjustment for creatinine
(MBPLM/Cr), correlates well with black hole volume (BHL VOL) detected on T1-weighted
cranial MRI, especially in SP MS and, more specifically, in those without
relapses and with more advanced disease.
PATIENTS, MATERIALS, AND METHODS
PATIENTS
The North American Linomide Study was a phase 3 trial of patients with
RR and SP MS conducted in 27 centers in a randomized, double-blind, placebo-controlled
and multidose fashion.28, 29 Of
718 patients entering the trial, 24-hour urine specimens were obtained from
662 patients at enrollment (Table 1).
The study population was 95.2% white and 4.8% nonwhite, with a female-male
ratio of 1.9:1. Of the 662 patients, 86 had RR MS, and 576 had SP MS.3 Of the group with SP MS, 317 were noted to have accompanying
relapses and 259 to have no relapses. All patients were scored as to disability
on the Expanded Disability Status Scale (EDSS).30
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Table 1. Correlations of Urinary Myelin Basic Protein–Like Material
and Black Hole Volume on Cranial Magnetic Resonance Imaging in Multiple Sclerosis*
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PERFORMANCE AND ANALYSIS OF CRANIAL MRI
Cranial MRIs were performed at the time of enrollment. All patients
underwent imaging (Signa 1.5-T scanner; General Electric, Milwaukee, Wis)
using version 5.4 or higher operating system, according to a defined protocol.29 Sequences were applied to obtain T2-weighted, fluid-attenuated
inversion recovery and magnetization transfer, T1-weighted with gadolinium,
magnetic resonance angiography, and postgadolinium T1-weighted images.29 Automated segmentation analysis was performed, and
a composite score was derived.31 Low-signal
intensity lesions, designated as "black holes," were determined by expert
identification and local thresholding on postgadolinium T1-weighted magnetization
transfer images.29 Black holes measure a heterogeneous
population of lesions. They were segmented based on having an intensity less
than that of the normal-appearing white matter and greater than that of cerebrospinal
fluid on the post–T1-weighted images. Black holes appear to include
the most permanent and least reversible tissue destruction, especially when
gadolinium-enhanced tissue is excluded as was done in this study.29 As noted,29 determination
of BHL VOL was not part of the original study design, and these determinations
on the MRI data obtained were not initiated until well after the study was
begun.
In an attempt to compile the various abnormalities detected on cranial
MRI, an MRI composite score, designated as the composite Z4, was determined.29 The Z4 was derived from the volume of enhanced tissue,
the normalized plaque volume, the normalized cerebrospinal fluid volume, and
the BHL VOL. The more positive the Z4 number, the worse the subject is on
MRI relative to his/her peers.
DETERMINATION OF URINARY MBPLM
At the time of preenrollment, a 3-L plastic bottle was issued to the
patient, who, during the 24 hours before the enrollment or second study visit,
collected his/her urine. The total volume and duration of collection were
determined, and, after thorough mixing, an aliquot of 25 mL of urine was placed
in a plastic container (Boritex; Fisher, Suwanee, Ga) with 1 boric acid tablet.
The vial was sent to the central laboratory of Quintiles, the contact research
organization for the trial, stored frozen at -20°C, and subsequently
shipped frozen to the laboratory of the primary author (J.N.W.) for analysis.
Studies were conducted (data not shown) to demonstrate that this processing
of urine did not alter the quantitative results of urine MBPLM.
Urinary MBPLM was determined by a double-antibody radioimmunoassay in
which radiolabeled human MBP peptide 69-89 served as the radioligand, rabbit
(R110) anti-MBP served as primary antibody, and human MBP peptide 83-89 served
as assay standard.21, 22, 23
The performance, validation, and variation of this radioimmunoassay have been
described elsewhere.22, 23 Urinary
MBPLM was expressed as nanograms per milliliter of unprocessed urine or as
nanograms per milligram of creatinine measured by standard methods.21 The statement of MBPLM in relationship to creatinine
was to use creatinine as an adjustment for renal function and dilution of
urine. Since 24-hour urine collections were made, 24-hour values of MBPLM,
designated as total MBPLM, were also calculated.
BIOSTATISTICS
All correlations were performed on the comprehensive clinical and MRI
data set available from the entire study29
and the measurement of urinary MBPLM. Because of the early termination of
the trial due to cardiac toxic effects, only a cross-sectional study was performed.
Statistics mentioned for the cranial MRI results have been previously reported.29 For the analyses and correlations of the urinary
MBPLM data, group and subgroup comparisons were made primarily by using the
general linear model approaches of analysis of variance with post hoc comparisons.
Correlations were performed using Pearson or Spearman rank procedures where
appropriate.
RESULTS
In this cross-sectional study, urinary MBPLM and MBPLM/Cr showed no
differences in the population of patients with an EDSS score of 5.0 or lower
or an EDSS score of 5.5 or higher, whereas BHL VOL was greater (P = .02) in the group with the higher EDSS scores ( 5.5).
A series of correlations were made for BHL VOL (Table 1) and the MRI composite Z4 score (Table 2) with urinary MBPLM. A weak direct correlation existed between
the level of urinary MBPLM and BHL VOL in all patients with MS (Table 1). The fact that the correlations with MBPLM were not evident
or as strong with MBPLM/Cr or total MBPLM presumably reflects the lack of
linearity of the measurement of MBPLM using a standard of MBP peptide 83-89.21, 22 When analyzed among MS subtypes,
this correlation was restricted to those with SP MS, specifically those without
relapses, and most significantly when the EDSS score was 5.5 or higher. The
later correlation was highly significant regardless of the manner in which
urinary MBPLM was expressed (Table 1).
The greatest significance was for urinary MBPLM/Cr. The group of patients
with SP MS with relapses showed no differences in urinary MBPLM related to
EDSS scores of 5.5 or higher or less than 5.5 in regard to T1-weighted BHL
VOL.
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Table 2. Correlations of Urinary Myelin Basic Protein–Like Material
and Z4 Score (Magnetic Resonance Imaging Composite) on Cranial Magnetic Resonace
Imaging in Multiple Sclerosis*
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The population of patients studied was predominantly white, but no racial
differences in the correlations were noted (data not shown). For correlations
of MBPLM or total MBPLM, there were no differences between sexes; however,
for MBPLM/Cr, in the group of patients with SP MS (92 females and 46 males),
both females and males showed the same correlations, which were more significant
for females. This is presumably related to the known lower body mass and urinary
creatinine in females.32
Although not as strong, similar correlations were noted between the
expressions of urinary MBPLM and the MRI composite Z4 score (Table 2). No racial or sex differences were noted. Since BHL VOL
is included in the Z4 composite score and since there was no significant correlation
of urinary MBPLM and any of the other cranial MRI measurements (data not shown),
this weaker relationship of the Z4 score and urinary MBPLM is presumably due
to the impact of the BHL VOL component on the composite score. The composite
Z4 score (Table 2) but not the
BHL VOL measurement (Table 1)
showed a weak correlation with MBPLM in patients with SP MS. This significant
relationship of Z4 was present only in those with an EDSS score of 5.5 or
higher. The correlation with the Z4 score and not with BHL VOL implies an
impact of another component, not yet identified, on the composite Z4 score.
No correlations for urinary MBPLM and any of the cranial MRI measurements
were detected for the RR MS group.
COMMENT
This investigation revealed that in patients with more advanced MS,
that is, those with an EDSS score of 5.5 or higher and without relapses, urinary
levels of MBPLM are significantly correlated with BHL VOL hypointense areas
on T1-weighted images on cranial MRI. The slightly less strong correlation
of urinary MBPLM with the MRI composite Z4 score is most likely the result
of the inclusion of other MRI methods, along with BHL VOL, in that composite.
These findings, an extension of previous studies relating increased levels
of urinary MBPLM to the progressive phase of MS,22, 23, 24, 27
provide additional evidence for the possible utility of urinary MBPLM to predict
or reflect the more disabling form of MS. The recent identification of p-cresol
sulfate as the major component of urinary MBPLM should facilitate the development
of improved detection methods for MBPLM and other clinical or neuroimaging
correlations.
Restriction of a significant correlation between urinary MBPLM and BHL
VOL to patients with SP MS with an EDSS score of 5.5 or higher to those without
relapses and not to patients with SP MS with relapses implies a pathological
difference between the clinical expressions of relapses and progression. The
varying combinations of the temporal events of relapses, remissions, and progression
constitute the basis for the clinical subtypes of MS currently recognized.
Cranial or spinal MRI features of these subtypes have not yet been clarified.
The distinction of the relationship of T1-weighted BHL VOL and urinary MBPLM
between SP MS patients with and without relapses adds to other unexplained
observations of the varied histopathological tissue alterations in MS33 and the apparent separate processes for T2 and gadolinium-enhancing
T1 lesions on cranial MRI.
The multicenter, phase 3 trial of Linomide was well designed to detect
beneficial treatment changes in RR MS and SP MS effected by Linomide. Unfortunately,
cardiac toxic effects led to termination of the trial shortly after full enrollment.28 Although there was a trend for improvement, especially
at the medium dose of Linomide of 2.5 mg/d, persuasive effectiveness of treatment
could not be demonstrated with the brevity of the trial.28
Nevertheless, important experience was gained from that trial. As reported
elsewhere,29 there was evidence of slowing
of progressive accumulation of lesion burden and of gadolinium positivity
in patients who were treated with Linomide compared with placebo. In addition,
the MRI measurement of BHL VOL also showed an effect of treatment. After 3
months of treatment in this trial, the proportion of lesions categorized as
black holes was reduced by treatment, with the effect most prominent for patients
with MS taking higher doses of drug (P<.05 for
active treatment and P<.03 overall).29
The biological relationship of BHL VOL on T1-weighted MRI appears to
be that of axonal loss and central nervous system tissue atrophy.14 Axonal damage, previously demonstrated in MS but
inferred to be less obvious or occurring later in the course of MS, has more
recently been shown to be an early accompaniment of inflammatory demyelination.34 The amount of atrophy that must exist in central
nervous system tissue to be detected by either a decline in N-acetylaspartate by magnetic resonance spectroscopy16, 17, 18, 19
or by increase in hypointensity on T1-weighted cranial MRI is unknown.14 It is clear that in normal-appearing white matter
the N-acetylaspartate is diminished when no abnormalities
are detected on MRI.35 Thus, among the measurements
that can be readily made in patients with MS to include magnetic resonance
spectroscopy, cranial MRI, and body fluid collections and subsequent measures,
there may be a useful and feasible means to monitor changes at different times
in the temporal profile of the early, middle, and late phases of MS and to
acquire an earlier indication of beneficial or nonbeneficial results of new
treatments.
AUTHOR INFORMATION
Accepted for publication May 5, 2000.
This investigation was supported by the research program of the Veterans
Administration, Washington, DC, and also by Pharmacia and Upjohn, Kalamazoo,
Mich.
Preliminary results of this study were presented at the 51st Annual
Meeting of the American Academy of Neurology, Toronto, Ontario, April 21,
1999.
Jeanine Goodwin provided excellent technical assistance, and Linda Brent
and Denise Ball furnished excellent assistance in the preparation of the manuscript.
Participants in the North American Linomide Trial
MRI–Analysis Center Assistants
MRI–Analysis Center, University of Texas Health
Science Center, Houston: Jonathan Carlson, Jennifer Chambers, Brian
Decuir, Lucy Mendia, Skipp Slattenow, Tom Thomas.
The North American Linomide Investigators
University Hospital (University of Alabama, Birmingham): John N. Whitaker, MD (clinical principal investigator), Galen W. Mitchell,
MD, Christopher C. LaGanke, MD, Beverly Layton, RN, University of Alabama,
Birmingham, MR Imaging, Taher El-Gammal, MD (imaging principal investigator),
Cleve Crews, Wladyslaw T. Sobol, PhD; Arizona Health Sciences
Center, Tucson : William A. Sibley, MD (clinical principal investigator),
Scott Sherman, MD, Barbara Geisser, MD, Jean Kunkel-Thomas, MD, Janet Mar,
RN, Todd McGregor, University Medical Center MRI, Joachim Seeger, MD (imaging
principal investigator), Joseph Berg, Arthur Gmitro, PhD, Bill Ahern; The Bowman Gray School of Medicine, Salem, NC: Douglas
R. Jeffrey, MD (clinical principal investigator), B. Todd Troost, MD, D. Leftkowitz,
MD, William McKinney, MD, Lorraine Harris, RN, MRI Center, Department of Radiology,
Allen Elster, MD (imaging principal investigator), Lisa Smith, Elaine James; Buffalo General Hospital, Buffalo, NY: Lawrence Jacobs,
MD (clinical principal investigator), Reza Pordell, MD, Frederick E. Munschauer
III, MD, Elizabeth Doherty, MD, Steven J. Greenberg, MD, Susan Krantz, RN,
Roswell Park MRI, Henry Z. Wang, MD, PhD, Wendy Zimmer, MD (imaging principal
investigators), Carol Kaminski, Richard Mazurchek, PhD, Mark Smerka; The University of Calgary: Luanne Metz, MD (clinical principal
investigator), David Patry, MD, Robert Bell, MD, W. F. Murphy, MD, Amanda
Pitts, RN, Sandra McGuinness, MN, Magnetic Resonance Imaging Centre, Foothills
Hospital, Carla Wallace, MD (imaging principal investigator), Pierre LaForge,
RTNM, Ken Bott; The University of California, Davis Medical
Center, Davis: Mark A. Agius, MD (clinical principal investigator),
David Richman, MD, N. Vijayan, MD, Lee Eun Kyu, MD, Janelle Adams, RN, University
of California, Davis Medical Center, MRI Center, Michael Buonocore, MD, PhD
(imaging principal investigator), Stephen Hecht, MD, Cindy DuPreeThompson,
Lisa Wall, Jose Gacayan, John Tinker, John Ryan, Danna Whitfield, David A.
Weber, PhD, Jim Deal; The University of California at Los
Angeles: Lawrence Myers, MD (clinical principal investigator), Joanna
Girard, MD, Robert Baumhefner, MD, Louis Rosner, MD, Sharon Craig, RN, UCLA
MR Imaging Center, John R. Bentson, MD (imaging principal investigator), Valerie
Gausche, BRST, Mary Ann Burns, CRT, Angela Wallace, CRT, Shantanu Sinha, PhD; The University of Chicago, Chicago, Ill: Anthony Reder,
MD (clinical principal investigator), Avertano Noronha, MD, Barry Arnason,
MD, Gwen Jacobs, RN, The University of Chicago Hospital Department of Radiology,
Daniel Huddle, DO (imaging principal investigator), Vence Edmonds, Robert
Meyers; Georgetown University Medical Center, Washington,
DC: John Richert, MD (clinical principal investigator), Carlo Tornatore,
MD, Kiren Kresa Reahl, MD, Jorge Kattah, MD, Andrew Pachner, MD, Tara Gustafson,
Shady Grove MRI, Robert Isaacs, MD (imaging principal investigator), Joe Previte,
Kevin Quinn; University Hospital, London, Ontario:
George Rice, MD (clinical principal investigator), George Ebers, MD, Pejjx
Wilma Koopman, University Hospital Imaging, Donald Lee, MD (imaging principal
investigator), Karen Kennedy, RTNM, Brian Rutt, PhD; Maimonides
Medical Center, New York: Aaron Miller, MD (clinical principal investigator),
Marshall Keilson, MD, Kersti Bruining, MD, Ellen Drexler, MD, Linda Sciarra,
RN, MSc; The New York Hospital–Cornell Medical Center,
New York: Brian Apatoff, MD (clinical principal investigator), Barry
Singer, MD, Justine Wheatley, RN, Priscilla Periconi, MPA, The New York Hospital–Cornell
Medical Center Imaging, Michael D. F. Deck, MD (imaging principal investigator),
John A. Markisz, MD, PhD, Michael Aquilia, RT; The University
of Maryland Hospital, Baltimore: Christopher Bever, Jr, MD (clinical
principal investigator), Kenneth P. Johnson, MD, Omar Khan, MD, Hillel Panitch,
MD, Suhayl Jalbut, MD, Eleanor Katz, RN, Cathy Conway, RN, Anna Gudusky MRI
Center, Michael Rothman, MD (imaging principal investigator), Erma Owens,
Moriel Nessaiver, PhD, Steve Crum; MCP Hahnemann University: Fred D. Lubin, MD (clinical principal investigator), Flo Trantas,
RN, Leith Kelly, RN, PhD, Thomas Jefferson University, Philadelphia,
Pa: Robert Knobler, MD, Jefferson Imaging–Bala, Carlos Gonzalez,
MD (imaging principal investigator), Lynn Adinolfi, BSRT(R), Simon Viniski,
PhD, Keith Kodash; Mayo Clinic, Rochester, Minn:
John H. Noseworthy, MD (clinical principal investigator), Claudia Lucchinetti,
MD, Brian Weinshenker, MD, Moses Rodriguez, MD, Andrea Adams, MD, Mindy Arneson,
RN, Mayo Clinic MR Imaging, Bradley J. Erickson, MD, PhD (imaging principal
investigator), John Rasmusson, Joel P. Felmlee, PhD, Richard Westlund; Mayo Clinic, Scottsdale, Ariz: Jonathan L. Carter, MD (clinical
principal investigator), Richard Caselli, MD, Kathryn J. Hirschorn, MD, Timothy
J. Ingall, MD, Alycia Metcalf, RN, Carrie Meshulam, CA, MRI Center, Kent D.
Nelson, MD (imaging principal investigator), Kay Dinoncourt, Dan Peterson; The Mellon MS Center–Cleveland Clinic, Cleveland, Ohio: Jeffrey Cohen, MD (clinical principal investigator), Thomas Masaryk,
MD, Bianca Guttman, MD, Revere P. Kinkel, MD, Richard Rudick, MD, Patricia
Adler, RN, MSN, Lakewood MRI Center, Jeffrey S. Ross, MD (imaging principal
investigator), Judy Wilms, RT, Jean Tkach, PhD, Steve Bowers; The University of Minnesota, Minneapolis: Gary Birnbaum, MD (clinical
principal investigator), Randall Shapiro, MD, David Knopman, MD, Crispin See,
MD, Rosemary Nelson, RN, Midwest MRI, David Kispert, MD (imaging principal
investigator), Kimberly Carley, Pat Miller, John Gaughan; Montreal Neurological Institute: Gordon Francis, MD (clinical principal
investigator), William Barkas, MD, Yves Lapierre, MD, Rozie Arnaoutelis, Montreal
General Hospital, Raquel Del Carpio-O'Donovan, MD (imaging principal investigator),
Laurian Rohoman, Christopher Henri, Gennare Durante; UMD
New Jersey Medical School, Newark: Stuart Cook, MD (clinical principal
investigator), Shalini Bansil, MD, Mary Ann Picone, MD, Annette Jotkowitz,
James Quinless, Department of Radiology, Leo J. Wolansky, MD (imaging principal
investigator), Janice Comiskey, Wen Ching Liu, PhD; The
University of Rochester Medical Center, Rochester, NY: Andrew Goodman,
MD (clinical principal investigator), David H. Mattson, MD, PhD, Steven R.
Schwid, MD, Eileen Scheid, RN, Department of Radiology, David Shrier, MD (imaging
principal investigator), Constance H. White, BSRT, Edmund Wing-Chi Kwok; Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill:
Dusan Stefoski, MD (clinical principal investigator), Floyd A. Davis, MD,
Karyn Karlin, MD, Jean Rush, RN, Greg Podraza, RN, ARSC–Circle Imaging
Center, William Greenlee, MD (imaging principal investigator), Ginny Flynn,
RT, Jin-Zhao Wang, PhD, Brad Phillips; St Michael's Hospital,
Toronto, Ontario: Paul W. O'Connor, MD (clinical principal investigator),
Trevor Gray, MD, Paul Marchetti, MD, Julie Hall, Sunnybrook Health Science
Center MRI Centre, Gordon Cheung, MD (imaging principal investigator), Pauline
Houston; University Medical Center SUNY at Stony Brook: Patricia K. Coyle, MD (clinical principal investigator), Lauren Krupp,
MD, O. Gerber, MD, Carol Doscher, NP, Department of Radiology, Robert G. Peyster,
MD (imaging principal investigator), Robert Day, Haifang Li, PhD, Christopher
Runz; The University of Texas–Houston, Health Science
Center: J. William Lindsey, MD (clinical principal investigator), Staley
Brod, MD, Mazen Dimachkie, MD, Emily Cerreta, RN, MSN, Hermann Hospital MRI
Department, Larry Kramer, MD (imaging principal investigator), June Garcia,
RT, Scot Duncil, RT; Vanderbilt University Medical Center,
Nashville, Tenn: Jane E. Howard, MD (clinical principal investigator),
Subramanian Sriram, MD, Howard Kirshner, MD, Renee Browning, RN, Vanderbilt
University Magnetic Resonance Imaging, Robert Kessler, MD (imaging principal
investigator), Richard Paulsen, MD, Ric Andal, Joe Knuutila, Ronald R. Price,
PhD, Dan West; Wayne State University School of Medicine,
Detroit, Mich: Robert P. Lisak, MD (clinical principal investigator),
Alex C. Tselis, MD, PhD, John Kamholtz, MD, PhD, James Garbern MD, PhD, Richard
Lewis, MD, Linda Tvardek, RN, Children's Hospital of Michigan, Cristie J.
Becker, MD (imaging principal investigator), Barbara Peters, Greg Moore.
External Data Safety Monitoring Committee
Henry McFarland, MD, Chair; Walter H. Carter, Jr, PhD, Charles Flexnor,
MD, Stephen L. Hauser, MD, John Petkau, PhD, Stephen Reingold, PhD.
Pharmacia and Upjohn
Per Gjörstrup, MD, Director of Clinical Research; Anders Linde,
MB, Study Director; Herman Sullivan, MD, Clinical Program Leader.
Reprints: John N. Whitaker, MD, Department of Neurology, University
of Alabama at Birmingham, 625 19th St S, Birmingham, AL 35233-7340 (e-mail: jnwhit{at}uab.edu).
From the Departments of Neurology (Dr Whitaker) and Biostatistics (Dr
Bartolucci), University of Alabama at Birmingham; Neurology and Research Services,
Birmingham Veterans Administration Medical Center (Dr Whitaker); Departments
of Neurology (Dr Wolinsky) and Radiology (Dr Narayana), University of Texas
at Houston Health Science Center; Department of Neurology, Mayo Clinic, Rochester,
Minn (Dr Noseworthy); Department of Neurology, Allegheny University of the
Health Sciences, Philadelphia, Pa (Dr Lublin); and Pharmacia and Upjohn, Kalamazoo,
Mich (Drs Gjörstrup and Sullivan and Mr Linde).
Reprints: John N. Whitaker, MD, Department of Neurology, University
of Alabama at Birmingham, 625 19th St S, Birmingham, AL 35233-7340 (e-mail: jnwhit{at}uab.edu).
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