**1. Introduction**

224 Advances in the Biology, Imaging and Therapies for Glioblastoma

Yung WK.; Luna M. & Borit A (1985). Vimentin and glial fibrillary acidic protein in human

Brain cancer is a life threatening neurological disorder in which malignant cells, grow, proliferate and invade the original cerebral structures of the host, hampering seriously adequate brain function. Malignant cells generate eventually a dedifferentiated tumoral mass that interferes with vital brain functions as sensory and motor activations, memory and perception and neuroendocrine regulation, among others. The fully developed tumoral mass consumes a significant part of cerebral volume resulting in cerebral compression and serious neurological impairments, such as vision or hearing disturbances and eventually lethal cerebrovascular complications. Most brain tumors remain asymptomatic during early development, revealing their symptoms and lethal nature only at later stages. Therapy is facilitated many times by an early finding, a circumstance making the neuroimaging approaches particularly useful in the detection and handling of these lesions.

In the last decades, Magnetic Resonance Imaging (MRI) approaches have evolved into the most powerful and versatile imaging tool for brain tumor diagnosis, prognosis, therapy evaluation, monitoring of disease progression and planning of neurosurgical strategies. MRI methods enable the non invasive assessment of glioma morphology and functionality providing a point of likeness into histopathological grading of the tumor and helping in this way a more successful patient management. This impressive evolution is based not only for the high resolution and quality of the anatomical images obtained, but on the additional possibilities to achieve quantitative functional information on tumoral physiopathology and its repercussions in the sensorial, motor and integrative functions through the brain. The use of conventional paramagnetic or superparamagnetic contrast media allows for the identification of areas with blood-brain barrier (BBB) disruption and the recent molecular imaging approaches enable researchers to visualize molecular events associated to tumor proliferation and invasion, bringing the potentials of diagnostic imaging to the cellular and molecular aspects of tumor biology. Moreover, functional MRI approaches as performed in the clinic are endowed with the potential to detect and characterize the earliest neoangiogenic, metabolic and hemodynamic alterations induced by the neoplasm.

Several advanced magnetic resonance (MR) methodologies have been proposed in the last years to assess the functional competence in healthy and pathologic brain tissue. Diffusion and perfusion MRI are probably the two main approaches that have reached a relevant clinical role

unambiguously this information. In spite of this, many of the histopathological features of gliomas are amenable to MRI explorations. In particular, the growth rate and the appearance of necrotic zones may be followed by sequential morphological MRI examinations, the cellularity and tumor microstucture investigated by diffusion weighted MRI, the compression effects of the tumor on surrounding neuronal tracts of the white matter may be examined by MRI tractography from DTI approaches and the development of the neoangiogenic vasculature characterized by perfusion imaging. These properties entail the MRI method with unprecedented capabilities to asses non invasively glioma grade and its potential repercussions. In the following sections we shall provide a description of main physical principles underlying these methodologies and provide illustrative examples

(a) (b) (c)

haematoxylin/eosin staning. (a) WHO grade II astrocitoma , (b) WHO grade III anaplastic

The diffusion phenomenon describes quantitatively the random (Brownian) molecular motion translations of water molecules originating ultimately from thermal energy. In a tissue, like the brain, the mechanism of diffusion involves mainly the motion of water molecules on a scale of 5 to 15 micrometers over the approximate 40 ms of measurement time. It is described by an Apparent Diffusion Coefficient (ADC), representing the average translational displacement of a water molecule during a time unit. The diffusion process has a vectorial nature, involving magnitude and direction. Its magnitude and direction in vivo depend on a variety of factors including permeability barriers and their spacing, microviscosity of the intracellular milieu, molecular obstructions to water displacements, duration of the diffusion measurement and, eventually the bulk flow within capillaries and water active transporters in tissue. These circumstances make the interpretation of diffusion measurements complex, but at the same

In vivo Diffusion Weighted Imaging (DWI) provides images with an inherent contrast different from that obtained by conventional structural MR techniques. In this sense, DWI gives unique information about the microstructure and viability of brain tissue, with the signal intensity of the image depending on the average translational motion of water molecules, an aspect known to be appreciably modified in cerebral tumors (Schaefer, Grant et al. 2000).

The first description of a diffusion study was provided by Stejskal and Tanner, who used a spin-echo acquisition protocol in which two gradient pulses equal in magnitude but

Fig. 1. Histopathological features from gliomas of increasing grade as revealed by

astrocytoma and (c) WHO grade IV glioblastoma multiforme

**3. Diffusion magnetic resonance imaging** 

time highly informative on all the aspects influencing it.

**3.1 Apparent Diffusion Coefficient** 

on their applications.

in brain oncology, particularly in neovascular imaging (Calli, Kitis et al. 2006). The diffusion approaches investigate the thermally induced random molecular motions of water molecules in tissues. The perfusion phenomenon describes and quantifies the microvascular blood flow which feeds a volume element of an organ or tissue. At a first glance these two phenomena seem to be very different, however a closer look identifies they both concerned with underlying molecular motions. Moreover, the random distribution of capillaries in tissues such as brain, provides tissue perfusion with some of the characteristic features of diffusive motion.

This chapter will summarize the arsenal of MRI approaches providing functional information on gliomas based on diffusion and perfusion MRI methods. We begin with a description of the pathological classification of gliomas and its implications for MRI diagnosis, continuing with the applications of diffusion weighted imaging (DWI), diffusion tensor imaging (DTI) and tractography to the characterization of these brain tumors. We conclude showing the MRI methodologies available for the evaluation of cerebral and tumoral perfusion, addressing the use of Dynamic Susceptibility Contrast (DSC), Dynamic Contrast Enhanced (DCE) MR images and Arterial Spin Labelling (ASL). Our review focuses mainly in the clinical applications of these methodologies, providing a brief introduction into the physical principles of each one. For interested readers, the following review articles provide more detailed descriptions of the corresponding physical principles of diffusion weighted (DW) MRI (Mori and Barker 1999), DTI (Basser and Jones 2002) and Tractography (Mori and van Zijl 2002) or the different approaches to investigate microvascular perfusion (Ostergaard 2005; Detre, Wang et al. 2009; Larsson, Courivaud et al. 2009).
