The Potential Value of Iron Oxide Nanoparticles in Brain

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                       The Potential Value of Iron Oxide Nanoparticles
                                 in Brain Tumor Treatment
   Dr Neuwelt and his coworkers have continued their                 have concluded from previous studies in rodents that
efforts to define the biological activity and possible clin-         iron oxide nanoparticles seem to have a similar volume
ical utility of dextran-coated iron oxide nanoparticles in           of distribution after direct injection into the brain as
imaging and therapy. Previous investigators have fo-                 adenoviruses and a similar ability to get into the intra-
cused on use of these particles in imaging and quan-                 cellular compartment as adenovirus and herpesvirus
titating the transport across a disrupted blood-brain                through a blood-brain barrier. Because, in this study in
barrier and in studying the distribution of convection-              humans, the iron oxide particles accumulated in tumor
delivered fluid in the brain interstitium. The use of iron           and normal brain in both the interstitial space and in-
nanoparticles has also been considered in MR angiog-                 tracellular compartment, the authors postulate that the
raphy; lymph node imaging; and target-specific imaging,              iron oxide particles might be a valuable tracer for the
in which they are conjugates to antibodies.                          transvascular or interstitial delivery of viral vectors.
   In the article in this issue of the AJNR, Neuwelt et al              However, the animal data that are used to compare
(see article by Varallyay et al) eliminated the use of               the movement of iron oxide particles to that of viruses
Feridex, in its currently allowed doses, as an agent in              to and through the brain is far from conclusive. The
the clinical imaging of brain tumors because of its                  proteins on the surface of viruses make their move-
inability to breach an disrupted blood-brain barrier.                ment past cell-surface receptors exceedingly complex.
Ferumoxtran-10 (Combidex), likely because of its                     As a result, the distribution of viruses through brain
smaller and more uniform particle size and its more                  tissue is somewhat unpredictable compared with that
complete dextran coat, passes the incompetent blood-                 of inert iron particles. Recently, several groups, study-
brain barrier and is trapped intracellularly. There-                 ing the potential of delivery of adeno-associated vi-
fore, ferumoxtran-10 can serve as a contrast agent for               ruses for gene therapy by using convection-enhanced
MR imaging; but the evidence reported here does not                  delivery at slow infusion rates, have indirectly shown
support its replacement of gadolinium as the contrast                the interaction of viruses with cells in the brain inter-
agent of choice in brain tumor imaging; ferumoxt-                    stitium. In these studies, the coinfusion of either man-
ran-10 enhancement appears to be far more inconsis-                  nitol or heparin reduced the binding of viruses to cells
tent and variable than gadolinium enhancement.                       near the infusion site and allowed the viruses to move
   Ferumoxtran-10 has a prolonged enhancement                        further afield to improve the volume of distribution
timeline, with sharp delineation of tumor margins at
                                                                     and gene transduction.
24 hours after injection. These characteristics might
                                                                        The growing interest in gene therapy for brain tumors
make this contrast agent better than gadolinium-
                                                                     and the poor viral gene expression in brain tumor trials
based media when surgery with intraoperative MR
                                                                     to date has made the study of convection-enhanced
imaging is planned; gadolinium-based agents have the
                                                                     delivery and other methods of optimizing the distribu-
unfortunate quality of leaking from the blood or
across the blood-brain barrier into the surgical cavity              tion of viruses in the brain imperative. To be successful
and interfering with the image when it is administered               in these pursuits, the tracking of viruses and/or imaging
intraoperatively. An increasing number of dedicated                  of gene transduction is essential. In a promising ap-
MR imaging units are being placed in operating rooms                 proach developed at our center, a marker gene for
worldwide, and they are intermittently used during the               herpes thymidine kinase (HSV1-tk), is included in the
frequently prolonged course of brain tumor resection.                viral genome and co-expressed in the target cell. Then,
The use of long-lived agents such as ferumoxtran-10                  a radiolabeled marker substrate, 2 -fluoro-2 -deoxy-1-
might be appropriate in protracted operations if the                 beta-d-arabinofuranosyl-5-[(124)I]iodouracil (FIAU), is
preoperative administration and the clearance of the                 delivered. This substrate is metabolized by HSV1-tk,
agent from the blood before intraoperative imaging can               trapped within the transduced cell, and detected with
be timed correctly. Because intraoperative MR imaging                positron emission tomography. Because this approach is
is proving to be useful in evaluating the extent of the              used to directly image an expressed gene, it should be
resection of gliomas (particularly) and pituitary tumors,            superior to tracking the movement of iron particles,
the spotty and unpredictable enhancement with the iron               which can only model the movement of the viruses
oxide particles with these tumors is disappointing.                  without assessing their ability to express their genes
   As the authors point out, gene therapy has potential              intracellularly.
in the treatment of brain tumors and other disorders.                                                   PHILIP H. GUTIN, MD
The ability to predictably deliver the virus into the brain                          Memorial Sloan-Kettering Cancer Center
has been one of major clinical obstacles. The authors                                                            New York, NY

506     EDITORIALS                                                                           AJNR: 23, April 2002

             Subcortical Low-Intensity Areas on T2-Weighted Images: An
                 Uncommon Finding with a Common Explanation?
   In this issue of the AJNR, Lee and colleagues de-        the time course of SCLI, which may be observed for
scribe a finding, referred to as a subcortical low-         days to weeks after the onset of symptoms.
intensity (SCLI), on T2-weighted fast-spin-echo and            What about other potential causes of SCLI? The
fluid-attenuated inversion recovery (FLAIR) images          authors consider two causes in detail and reject both:
in patients with meningitis, viral encephalitis, or lep-    the accumulation of nonheme iron and a structural
tomeningeal metastases. For these clinical diagnoses,       change in the subcortical white matter. Abnormal
the frequencies of observation of the finding on ret-       iron accumulation in the extrapyramidal system is
rospective review of the MR images were 8.6% (five          generally accepted as the cause of excessive T2 short-
of 58 patients with meningitis), 23.7% (nine of 38          ening in the deep gray matter nuclei in several neu-
patients with viral encephalitis), and 23.8% (five of 21    rodegenerative diseases such as Parkinson disease
patients with leptomeningeal metastases). Interest-         and the Parkinson-Plus syndromes. T2 shortening in
ingly, cortical hyperintensity was observed in most         the subcortical white matter of patients with cerebral
patients (73.9%) and leptomeningeal enhancement             ischemia and infarction has also been attributed to
was observed in all of the 19 patients with SCLI areas;     iron deposition (secondary to disruption of axonal
the percentages were approximately double those ob-         transport of iron); however, the link between T2
tained in the cohort of patients without SCLI areas.        shortening and iron accumulation in the subcortical
   The striking features of SCLI lesions are the fol-       white matter is unproven, as Lee and colleagues note.
lowing: 1) focal-to-diffuse involvement of the subcor-      Although iron accumulation is an intriguing possibil-
tical white matter (unilateral, frontal and parietal        ity from the standpoint of the DWI findings, Lee and
lobes), 2) reversibility in patients with meningitis or     colleagues reject it as a cause of SCLI, primarily on
encephalitis, 3) isointense-to-hypointense signal on        the basis of conflicting reports in the literature, the
isotropic diffusion-weighted images (DWI), and 4)           transient nature of SCLI, and the lack of detectable
decreased apparent diffusion coefficients (ADCs)            iron on Perls staining of the biopsy sample obtained
(compared with values obtained from the contralat-          from the cortex and subcortical white matter in a
eral normal white matter) in half of the lesions eval-      patient with viral encephalitis.
uated with DWI (mean decrease of approximately                 The second postulated cause of SCLI that the au-
9%). On the basis of these observations, the results of     thors rejected may not be so easily dismissed without
a single biopsy that showed focal myelin pallor, and        additional histochemical and ultrastructural informa-
the results of studies by other investigators that have     tion. The statement that “no obvious evidence of
revealed the uncommon occurrence of SCLI-like               structural abnormality” is present on histologic exam-
areas in a variety of other pathologic conditions           ination is not exactly true because myelin pallor was
(eg, early cortical ischemia, multiple sclerosis, Sturge-   observed in the only biopsy specimen obtained. Al-
Weber syndrome), the authors conclude that SCLI is          though no histopathologic evidence of myelin catab-
a nonspecific sign of meningeal and cortical disease        olism (as it occurs in Wallerian degeneration) was
(although encephalitis is not an exclusively cortical       reported, could subtle ultrastructural changes in my-
disease) and that SCLI may be caused by a transient         elin be occurring in SCLI areas? It is curious that the
increase in the amount of free radicals.                    subcortical white matter signal intensity changes on
   Why free radicals? Free radicals, which are princi-      T2-weighted images in conditions as disparate as
pally reactive oxygen intermediates (eg, superoxide         Wallerian degeneration and Sturge-Weber syndrome
radical, hydrogen peroxide, hydroxyl radical) are           pass through a stage of hypointensity that is attribut-
transient and have been implicated in numerous              able to myelin metabolism. These conditions and the
pathologic processes, including brain edema, isch-          SCLI reported here differ, though in the time course
emia and infarction, meningitis, encephalitis, and ma-      of signal intensity changes (longer in Wallerian de-
lignancy. The last includes the processes that Lee and      generation and Sturge-Weber syndrome) and in the
colleagues reported. Furthermore, the oxygen free           eventual white matter destruction that occurs in Wal-
radicals are paramagnetic because of their unpaired         lerian degeneration.
electrons, and paramagnetic species can shorten the            With their study, Lee and colleagues raised more
T2 relaxation time, resulting in SCLI. The flaw in this     questions than they answered. This is often the case in
reasoning, of course, is that no cause and effect has       science. The answer to the question of whether the
been demonstrated. The implication of oxygen free           relatively uncommon finding of SCLI in various
radicals seems to be based on “guilt by association,”       pathologic conditions can be explained by a common
and the conclusion becomes problematic when the             mechanism must await more thorough and hypothe-
authors attempt to explain why no cortical low-inten-       sis-driven investigation. Certainly, more tissue speci-
sity areas are present and how the temporal expres-         mens should be obtained and analyzed, and conceiv-
sion of short-lived oxygen free radicals is related to      ably, an animal model may need to be developed to
AJNR: 23, March 2002                                                                           EDITORIALS          507

cytochemically demonstrate negative oxygen interme-          gations, though, one should also ask whether this
diates by using published techniques. The results of         nonspecific MR sign is of sufficient clinical benefit to
such laboratory investigations are more likely to an-        be worth the effort.
swer the questions raised in this article than addi-
tional clinical MR measurements of parameters such                                           BRIAN BOWEN, MD, PHD
as magnetization transfer ratios, T2 relaxation times,                                        Department of Radiology
or metabolite concentrations from in vivo proton                                            University of Miami School
spectroscopy. Before embarking on extensive investi-                                                        Miami, FL

                          How Can We Make BOLD Contrast Bolder?

   Functional magnetic resonance imaging (fMRI)              incomplete. This lack is reflected by the often-inconsis-
based on blood oxygenation level– dependent (BOLD)           tent reports on the dependence of local activation–
contrast is a noninvasive technique that offers an           related BOLD signal changes on the baseline BOLD
unprecedented opportunity to explore the neuronal            signal modulated by various approaches such as hyper-
basis of human cognition, perception, and behavior.          capnia, hypocapnia, and vasoconstrictive or vasodilatory
Despite extensive studies over the last decade, we still     drugs. The report of the animal study by Morton et al
have only a rudimentary understanding of the rela-           (1) in this issue of the AJNR represents another effort to
tionship between the BOLD fMRI signal and the                clarify the relationship between the local activation–
underlying neuronal activity. Understanding this re-         induced BOLD signal changes and globally modulated
lationship is important if we are to discover methods        baseline BOLD signal amplitude.
to increase the sensitivity of what is now a technique          In brief, the results from previous research are
with relatively low sensitivity, which has particularly      complex and sometimes confusing. The effect of
limited the application of fMRI in the evaluation of         global cerebral modulation (either vasodilation or
cognitive and psychiatric disorders.                         vasoconstriction) on the local activation–induced
   It is now generally accepted that the BOLD fMRI           BOLD response can be either up- or down-
signal changes in response to activation stimuli are         regulating, depending on the experimental setting.
related to the increase of regional cerebral blood flow      On the basis of the current understanding of the
(rCBF), which alters the relative local concentrations       BOLD effect, the activation-induced BOLD signal
of oxyhemoglobin and deoxyhemoglobin. However,               changes are dependent on both the rCBF response
little is known about the process by which focal neu-        and the cerebral metabolic rate of oxygen. If the
ronal activity triggers the increase in rCBF. A com-         activation-related rCBF response is assumed to be
plex system involving vasoactive substances, nitric oxide,   independent of the prevailing CBF level, as the
neurotransmitters, and intrinsic factors has been postu-     direct perfusion results from arterial spin-labeling
lated. In addition to this local coupling of rCBF with       fMRI studies (2) implicate, the observed variations
neuronal activation, CBF is also sensitive to factors        in the BOLD response under conditions of global
acting globally; these include perfusion pressure, the       cerebral vasodilation and vasoconstriction can only
partial pressures of CO2 and O2 in the cerebral circula-     be attributed to changes in the oxygen consump-
tion, and other biologic and pharmacologic variables.        tion. Quite possibly, CO2-, O2-, and drug-induced
   In view of these global perfusion regulatory sys-         global modulations of vasomotor tone may lead to
tems, the question of whether the increase in rCBF           different functional-metabolic couplings of tissue
during neuronal activity is linked to the baseline ce-       during task activation. However, the precise mech-
rebral blood flow arises. The clarification of the rela-     anisms underlying the effect of each agent on the
tionship between the baseline cerebral blood flow at         BOLD response is not yet well understood.
rest and the increase in rCBF as a result of focal              In this study, Morton et al (1) found that the systemic
neuronal activity may lead to a better understanding         administration of theophylline markedly increases the
of the processes underlying the BOLD response. It            BOLD response in rats. The findings from this study are
also has substantial practical relevance for the inter-      similar to the recent results of a study about the use of
subject comparison of BOLD signal intensity during           caffeine as a contrast booster for BOLD fMRI studies in
task activation. The dependency of the rCBF associ-          human subjects (3). Given the fact that caffeine and
ated with a neural activation on the prevailing cere-        theophylline belong to the same methylxanthine family
bral blood flow has been the focus of many functional        of drugs and that both drugs act as vasoconstrictors in
neuroimaging investigations.                                 the brain, the two drugs are likely to have the same
   For BOLD fMRI, changes in global cerebral blood           mechanism regarding the booster effect on BOLD con-
flow and rCBF are indirectly related to changes in ce-       trast. It was suggested that the enhanced BOLD sensi-
rebrovascular oxygenation, but this fact accounts only       tivity was possibly due to the increased concentration of
for a small fraction of the measured signal intensity on     deoxyhemoglobin at the resting state that results from
T2*-weighted images. Therefore, the physiologic basis        the reduced CBF during vasoconstriction. This interpre-
for the current analytical models of the BOLD signal is      tation is conceivable, but it fails to explain why vaso-
508     EDITORIALS                                                                               AJNR: 23, March 2002

constriction induced by indomethacin (4), for example,    trast boosters to overcome the low sensitivity of fMRI
attenuates the BOLD response. The neuroexcitability       technique might be possible; this improvement may
effect of these drugs offers another plausible explana-   make fMRI more applicable in clinical medicine.
tion for the resetting of the coupling between cerebral                                      TIE QIANG LI, PHD
blood flow and energy metabolism.                                                   VINCENT P. MATHEWS, MD
   A full understanding of why and how BOLD fMRI                                       Department of Radiology
signal is related to the underlying neuronal activity                      Indiana University School of Medicine
requires a great deal of further research. However,
this issue is very important because the ultimate suc-
cess of fMRI depends on the establishment of a spe-                                References
cific relationship between the fMRI signal and neu-
ronal firing activity. The characterization of the        1. Morton DW, Maravilla KR, Meno JR, Winn HR. Systemic the-
relationship between local BOLD response and the             ophylline augments the blood oxygen level– dependent response to
                                                             forepaw stimulation in rats. AJNR Am J Neuroradiol 2002;23:588 –
prevailing cerebral blood flow level modulated by            593
chemical agents is a promising approach that can          2. Li TQ, Kastrup A, Moseley ME, Glover GH. Changes in baseline
potentially elucidate the cascade of processes that          cerebral blood flow in humans do not influence regional cerebral
                                                             blood flow response to photic stimulation. J Magn Reson Imag
trigger rCBF change in response to task activation.          2000;12:757–762
Despite an incomplete understanding of the underly-       3. Mulderink TA, Gitelman DR, Mesulam MM, Parrish TB. On the
ing mechanisms, the study by Morton et al reveals a          use of caffeine as a contrast booster for BOLD fMRI studies.
significant increase in the BOLD response in rats by         Neuroimage 2002;15:37– 44
                                                          4. Bruhn H, Fransson P, Frahm J. Modulation of cerebral blood
using systemically administered theophylline. This           oxygenation by indomethacin: MRI at rest and functional brain
finding indicates that the development of BOLD con-          activation. J Magn Reson Imag 2001;13:325–334

           Intraosseous Venography during Percutaneous Vertebroplasty:
                                 Is It Needed?
   In the last 15 years, neuroradiologists in Europe      ment was not significantly different between the two
and America have pioneered the technique of percu-        groups. Interestingly, in 14 (64%) of 22 patients in the
taneous vertebroplasty for the treatment of pain and      group who underwent antecedent venography, correla-
decreased mobility associated with osteoporotic and       tive extravasation was shown with venography. The au-
pathologic vertebral-body compression fractures.          thors concluded that antecedent venography did not
Multiple reports in the medical literature detail the     significantly augment the effectiveness or safety of per-
clinical experience and technique of percutaneous         cutaneous vertebroplasty procedures performed by this
vertebroplasty. In this issue of the AJNR, Kaufmann       group of experienced interventional neuroradiologists.
et al (pages 601– 604) address a particular conundrum        When percutaneous vertebroplasty was initially
concerning the technique and performance of verte-        evaluated and performed in North America at the
broplasty by investigating the relevance of antecedent    University of Virginia beginning in 1993, antecedent
venography in percutaneous vertebroplasty for treat-      venography was an integral part of this procedure and
ment of osteoporotic compression fractures. Opin-         performed in every patient. In the initial report about
ions differ, and the utility of antecedent venogra-       the technique and the early clinical outcomes with
phy in determining improved clinical outcomes or          this technique in the treatment of painful osteopo-
decreased complications during vertebroplasty is          rotic compression fractures, Jensen et al (1) advo-
controversial. The authors retrospectively reviewed       cated the use of antecedent venography to decrease
results in consecutive patients treated with percu-       potential complications associated with incorrect or
taneous vertebroplasty for vertebral-body compres-        suboptimal needle placement in the basivertebral ve-
sion fractures. The first group of patients under-        nous plexus or in direct connection with a paraverte-
went antecedent venography, whereas the second            bral vein. The purpose is to delineate a potentially
group was treated without venography. The clinical        dangerous route by which PMMA cement might es-
outcomes were assessed by means of quantitative           cape the confines of the vertebral body. PMMA ce-
measurements of pain and mobility. The intraosseous       ment can escape posteriorly into the spinal canal,
venograms and postvertebroplasty radiographs were         causing spinal canal stenosis or cord compression; to
evaluated for extravertebral polymethylmethacrylate       the intervertebral foramina, causing nerve root com-
(PMMA) deposition, amount of extravasation at each        pression; or to the vena cava and pulmonary arteries,
treated level, and correlation between results with       causing pulmonary embolism. With a right-to-left car-
venography and results with vertebroplasty. The au-       diac shunt, such as that in patent foramen ovale or
thors found that improvements in pain and mobility        ductus arteriosus, a potential stroke may occur, al-
did not differ between the two treated groups. Simi-      though it may never be reported. This event may
larly, the demonstrated extravasation of PMMA ce-         necessitate needle readjustment or, as the authors
AJNR: 23, March 2002                                                                                   EDITORIAL              509

suggest, it may require the use of maneuvers to pre-       performance of vertebroplasty include correct patient
vent potential cement extravasation. Such maneuvers        selection; good knowledge of vertebral bony and vas-
include 1) the placement of Gelfoam pledgets prior to      cular anatomy; adequate opacification of PMMA ce-
injection of PMMA or 2) an initial deposition of           ment; and high-quality fluoroscopy, preferably with
PMMA and a period of waiting to allow the cement to        biplane types. Although the authors mention the issue
harden and obliterate the direct venous connection(s)      of excessive radiation exposure and the cost of con-
and then the use of a second needle to inject the          trast material in the performance of venography,
cement into the vertebral body. However, some au-          these are likely to have no clinical importance. To my
thors (2– 4) disagree with this approach and state that,   knowledge, no report of the adverse effects of venog-
due to differences in the viscosity and flow character-    raphy exists in the literature. The amount of contrast
istics of contrast material and cement, venographic        agent used per venogram is approximately 3–5 mL;
findings are not predictive of the actual flow of          therefore, the risk to patients with renal failure is
PMMA cement and path of extravasation. Addition-           minimal. The authors correctly point out that, in
ally, the persistence of intravertebral opacification      those adept at the performance of vertebroplasty,
could obscure visualization of cement, for example,        venography may represent a superfluous step. Venog-
during an injection into necrotic cavities in cases of     raphy, however, may be extremely beneficial for less
vertebral osteonecrosis or Kummell disease (5) or          experienced physicians. The use of intraosseous
during an injection through the endplates to the in-       venography should still be advocated during training
tervertebral discs. Preoperative imaging with demon-       courses, and its clinical value should be pointed out to
stration of intravertebral gas or a fluid collection       the trainees.
should alert one to the possibility of vertebral osteo-       The results of this study are valuable and thought
necrosis; therefore, the venographic procedure             provoking. As the authors acknowledge, the study is
should be modified by injecting contrast material          limited by its retrospective nature, and the sample
gently and by using the minimal volume of contrast         size may result in a lack of statistical power. Prospec-
agent (1–2 mL).                                            tive randomized trials to evaluate the effectiveness of
   Although venography may not augment the safety          vertebroplasty compared with that of sham-vertebro-
of vertebroplasty when it is performed by experienced      plasty and conservative medical treatment are under-
operators, it may guide novice or inexperienced op-        way. If possible, an evaluation of the value of ante-
erators and help them to perform vertebroplasty in a       cedent venography in these studies may provide
safer manner. In addition, although venographic find-      interesting results.
ings may not be absolutely correlated (64% in Kauf-
mann et al’s series) with the actual extravasation of                                                   HUY M. DO, MD
cement, the additional information that the delinea-                                    Stanford University Medical Center
tion of the venous anatomy around the vertebral body                                                         Stanford, CA
may potentially be of benefit. Percutaneous vertebro-
plasty is an intravascular procedure because the ver-
tebral bony trabeculae is a large venous space with                                   References
eventual connections to the draining veins. PMMA           1. Jensen ME, Evans AJ, Mathis JM, et al. Percutaneous polymeth-
cement should be considered to be a liquid embolic            ylmethacrylate vertebroplasty in the treatment of osteoporotic ver-
agent, and it should be treated and used with caution         tebral body compression fractures: technical aspect. AJNR Am J
and full knowledge of its possible adverse effects.           Neuroradiol 1997;18:1897–1904
                                                           2. Weill A, Chiras J, Simon JM, et al. Spinal metastases: indications
When the venograms are shown on separate moni-                for and results of percutaneous injection of acrylic surgical cement.
tors, these reference images may provide guidance in          Radiology 1996;99:241–247
the detection of early-appearing and small quantities      3. Gangi A, Kastler BA, Dietemann JL. Percutaneous vertebroplasty
                                                              guided by a combination of CT and fluoroscopy. AJNR Am J
of extravasated cement. Although cement extravasa-            Neuroradiol 1994;15:83– 86
tion does occurs, the volume and amount of extrava-        4. Mathis JM, Barr JD, Belkoff SM, et al. Percutaneous vertebro-
sation causes potential clinical complications. There-        plasty: a developing standard of care for vertebral compression
fore, the early detection and knowledge of cement             fractures. AJNR Am J Neuroradiol 2001;22:373–381
                                                           5. Do HM, Jensen ME, Marx WF, Kallmes DF. Percutaneous verte-
extravasation is the key to the safe performance of           broplasty in vertebral osteonecrosis (Kummell’s spondylitis). Neu-
vertebroplasty. Other important factors in the safe           rosurg Focus [serial online]. July 1999;article 2