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and 10 control aneurysms (superficial temporal DIRECT IN VIVO IMAGING OF INFLAMMATION
arteries) utilizing agilent microarrays. Critically,
utilizing hierarchical clustering and nonnegative The recent development of novel in vivo imaging
matrix factorization, the samples were classified techniques directly targeting specific immune cell
into homogeneous subgroups showing similar gene subsets and inflammatory enzymatic biomarkers allows
expression patterns. Focusing on ruptured IA in an early clinicians to quantitatively access the inflammatory
onset age (average age 46.6) sub group, and unruptured status of pathologically relevant tissue. [48] Given
IA allowed the investigators to note expressional the role of macrophages in IA pathogenesis, several
differences. They observed increased levels of markers studies conducted by Hasan et al. [49-52] investigated
for both macrophage infiltration (CD163) and oxidative the possibility of in vivo aneurysm wall macrophage
stress (myeloperoxidase). Significant increases in S100/ quantification through infusion of a carbohydrate
calgranulin expression, which acts through TLR-2 coated superparamagnetic iron oxide nanoparticle,
to recruit macrophages/monocytes and neutrophils, ferumoxytol (AMAG Pharmaceuticals, Lexington,
were similarly reported as selectively overexpressed in Massachusetts, USA). Ferumoxytol is cleared
early ruptured IA. TLR-6 that forms heterodimers with by macrophages in either the arterial lumen or
TLR-2, was also significantly overexpressed, ultimately subendothelium of IAs, thus allowing for delayed
suggesting this pro-inflammatory signaling pathway visualization of macrophage activity as a surrogate
is involved in IA wall inflammation and rupture. [43] biomarker for inflammatory status of a particular
Finally, Krüppel-like transcription factors (KLF) KLF-2, lesion. [53] The optimal imaging chronology for this
KLF-12, and KLF-15 were all down-regulated in the novel ferumoxytol enhanced MRI was found to be 5 mg/
early ruptured IA subgroup. KLF-2 is known to possess kg ferumoxytol with imaging at 72 h postinjection. [49] A
anti-inflammatory functionality. [44] This study was critical observation was made in a subsequent follow-up
the first to show distinct gene expression differences study. The authors found that the time of ferumoxytol
between early and late ruptured IA. In addition, uptake may be indicative of aneurysmal stability and
these data further implicate macrophage-mediated rupture propensity. Those exhibiting early uptake (24 h
inflammation in IA rupture. postinjection) ruptured within 6 months. Furthermore,
[51]
immunostaining of surgically resected aneurysm dome
Differential gene expression in peripheral blood has tissue revealed increased expression of COX-2, mPGES,
been observed in response to both brain arteriovenous and the number of M1 variety macrophages in aneurysms
malformations and abdominal aortic aneurysms. [45,46] with early uptake. It should be noted that this suggests
The first peripheral blood transcriptome analysis imaging beyond 24 h may prove unnecessary with
in patients with SAH from ruptured IA was respect to rupture risk stratification; however, 72 h
recently carried out by Pera et al. [47] The group remains the optimal timing for imaging macrophages in
found that the gene expression profile of venous the walls of IA’s. This time interval may still be used to
blood obtained prior to neurosurgical intervention access the efficacy of anti-inflammatory therapeutics. [51]
differed significantly from control patients who Additionally, previous studies that provided evidence of
did not harbor IA. The Illumina HumanHT-12 v4 inflammatory changes in ruptured aneurysms had fallen
microarrays revealed T-lymphocyte subpopulation short of providing evidence of its involvement prior to
specific transcripts were down-regulated, whereas rupture, rather than as a response to rupture. These
[5]
transcripts related to neutrophils and monocytes data, therefore, provide the first direct evidence that
were up-regulated. Based on these data, the authors inflammation is a causal factor in IA rupture progression.
developed a L/MN index, defined as the mean folds Finally, the group was able to use this novel noninvasive
of standardized peripheral blood expression levels technique to monitor the therapeutic effects of aspirin
of lymphocyte related genes against expression of as it curtailed the inflammatory progression of cerebral
neutrophil and monocyte related genes. This ratio aneurysms in human patients. [54] In this study, the
was statistically associated with clinical prognosis; findings of ferumoxytol enhanced MRI correlated well
the L/MN value was lower in patients who died with a subsequent immunohistochemical assessment.
[54]
during hospitalization compared with RA patients Taken together, these studies suggest that ferumoxytol
who survived. When blood gene expression profiles enhanced MRI may indicate active inflammation in
are compared with transcriptomic analyses of IA aneurysm walls and allow neurosurgeons to optimize
tissue, inflammation is the common denominator. [47] decisions regarding intervention or observation of
However, these inflammatory changes likely reflect a cerebral aneurysms.
systemic response to ruptured IA bleeding. These data
further suggest novel molecular biomarkers, which Recent histological evidence suggests that the
may prove beneficial for optimum management of myeloperoxidase, a secretable oxidoreductase
aneurysmal SAH patients. of azurophilic granules of polymorphonuclear

Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015 81