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Brain imaging in glaucoma from clinical studies to clinical practice
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Brain imaging in glaucoma from clinical studies to clinical practice
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Francesco Garaci*,1, Simone Altobelli†, Nicola Toschi{,}, Raffaele Mancino}, Carlo Nucci}, Orazio Schillaci{,k, Roberto Floris†,{ *Diagnostic Imaging Section, Tor Vergata University Hospital, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy † Diagnostic Imaging section, Tor Vergata University Hospital, University of Rome Tor Vergata, Rome, Italy { Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy } Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging and Harvard Medical School, Boston, MA, USA } Ophthalmology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy k IRCCS Neuromed, Pozzilli, Italy 1 Corresponding author: Tel.: +39-06-20902471; Fax: +39-06-20902471, e-mail address: [email protected]
Abstract Recent advances in Magnetic Resonance Imaging (MRI) technology have brought new insight in central nervous system (CNS) manifestation of glaucoma. New MR techniques allowed to identify in vivo and noninvasively alterations along all the visual pathway in both early and late stages of the disease. Conventional neuroimaging still plays an important role, mostly in the anatomy description and in the differential diagnosis with space occupying lesions but it should be supported by other advanced MR techniques such as diffusion tensor imaging, functional imaging (BOLD–ASL), and magnetic resonance spectroscopy, which offer the possibility to investigate deep white matter tracts integrity and cortical gray matter changes. In a future perspective, MR quantification of CNS damage associated with glaucoma will be of pivotal importance for prognostic stratification and evaluation of neuroprotective therapy response.
Keywords MR imaging, Diffusion tensor imaging, Glaucoma, MR spectroscopy, fMRI
Progress in Brain Research, Volume 221, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2015.06.004 © 2015 Elsevier B.V. All rights reserved.
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1 BACKGROUND Although one of the most important and well-known risk factor for glaucoma is increased intraocular pressure (IOP) (>21 mmHG), some patients present with normal IOP (often termed “normal pressure” or “normal tension” glaucoma). Further, in spite of regular IOP drug monitoring, a number of glaucomatous patients demonstrate a progression of both retinal ganglion cell and optic nerve degeneration. These aspects of glaucoma have suggested that the pathogenesis of the disease might be more complex than previously hypothesized. In this context, the manifestations of glaucoma (or at least of some subgroups) are not limited to the ocular bulbs but rather involve all optic pathways from bulb to cortex, hence including the brain. The first ex vivo data documenting human brain involvement in glaucoma have been published by Gupta et al. (Gupta and Yucel, 2006): in this important study, histopathology demonstrated a significant volume reduction of both the lateral geniculate nucleus (LGN) and the visual cortex as compared to controls. Successively, neuroimaging has been able to demonstrate that this “damage” can be quantified, in vivo and noninvasively, in all optic pathways (Garaci et al., 2009), opening an extraordinary and challenging field of research which has rapidly developed in the last 5–8 years. In this context, magnetic resonance imaging (MRI) was demonstrated to be the method of choice due to its ability to visualize the optic nerve and chiasm noninvasively and with excellent contrast; deep visual pathways can also be assessed with advanced MR techniques such as diffusion tensor imaging (DTI), functional imaging (BOLD–ASL), and spectroscopy. The purpose of this chapter is to critically review the literature documenting the use of MRI to evaluate glaucoma neuropathy. Current applied techniques and published results are discussed along with future perspectives and potential prospective applications in neuroprotective drug monitoring.
2 CONVENTIONAL MRI MRI allows rapid assessment of visual system anatomy including orbital structures such as the globe, the optic nerve and canal, retrobulbar adipose tissue, orbital muscles, and the apex (Fig. 1). Deeper structures like the chiasm and the optic tract can be also imaged accurately through morphological MR sequences. The rest of the visual pathway is more challenging to distinguish in conventional imaging and usually requires more advances techniques. Anatomical imaging is based on the tissuedependent differences in MR signal, which allow to distinguish, e.g., white or gray matter and cerebrospinal fluid (CSF). Morphologic sequences are conventionally employed as a first step to identify space occupying lesions or other pathologic processes of the visual system. The optic nerve is sheathed with leptomeninges and has a subarachnoidal space of 0.4–0.6 mm which is directly connected with its corresponding intracranial space. Its overall length is 50 mm and it can be divided in four segments: the intraocular
2 Conventional MRI
FIGURE 1 Axial T1 weighted images documenting the optic nerve segments and the orbital muscular cone anatomy.
(1 mm), intraorbital (25–30 mm), intracanalicular (6 mm), and intracranial segments (5–16 mm). The intraorbital segment is easily identifiable in MR images due to the contrast between nerve tissue and the surrounding adipose tissue of the orbit. In this context, T1-weighted 3D inversion recovery (IR) sequences are extremely useful because of their high signal-to-noise ratio and the possibility to reslice in all orthogonal planes. In general, macroscopical anatomy is best assessed using T1-weighted techniques (usually integrated with fat suppression techniques), in particular after Gadolinium administration which allows better visualization of contrast-enhanced intraorbital masses. T2-weighted sequences, in particular on the axial and coronal planes, are useful to visualize space occupying lesion or optic nerve atrophy. Glaucoma causes a loss of neural fibers within the optic nerve leading to a decrease of its size which is more pronounced at its distal level. Normal thickness values of the intraorbital segment of the ON range from 3.1 mm (anterior) to 2.5 mm (posterior), whereas the mean dural diameter ranges between 5.1 (anterior) and 2.8 (posterior). Thinning of the nerve and widening of its subarachnoidal space has been described in previous studies and has been correlated with the thickness of the nerve fiber layers using optical coherence tomography (OCT). For instance, Lagreze et al. (2009) used a HASTE ultrafast sequence on a 3T scanner documenting a significant correlation between ON diameter and OCT results. Similarly, Kashiwagi et al. (2004) documented that the optic nerve diameter was significantly smaller in glaucoma patients (2.25 0.33 mm) when compared to controls (2.47 0.24 mm). The chiasm and the optic tract are best identified with T1-weighted images, as demonstrated previously in Kashiwagi’s work was documented a reduction of the height of the optic chiasm in glaucoma patients (2.12 0.37 mm) compared with controls (2.77 0.36 mm) (Kashiwagi et al., 2004). The optic chiasm is clearly visible in T2-weighted images because it is surrounded by CSF in the chiasmatic cistern.
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Optical tract fibers close to the LGN as well as the LGN itself, where the third neuron of the visual pathway is located, are difficult to visualize in conventional MRI and their anatomy and pathology can only be evaluated approximately with T1-weighted IR sequences. Postgeniculate fibers and the optic radiation cannot be imaged with conventional morphological sequences ( Jacobs and Galetta, 2007); thus, more advances morphological processing techniques such as voxel-based morphometry (VBM) or diffusion-based imaging techniques such as DTI are necessary. Also, the overall contrast between gray and white matter allows the visual cortex to be distinguished on conventional imaging, however, its function and detailed anatomy is better described by advanced techniques. Lastly, the use of Gadolinium-enhanced T1 images is mandatory if inflammatory or neoplastic diseases are suspected across the whole visual system. In the context of contrast-enhanced imaging, new insights are likely to be provided by the use in humans of new manganese-based contrast agents which have been seen to clearly enhance the visualization of glaucoma-related changes in animals (Calkins et al., 2008). Angio-MRI of Willis circle, using the time of flight (TOF) technique without the administration of contrast material, is also needed to rule out extrinsic compression of the optic pathways (usually at the level of optic chiasm) by vascular malformations (e.g., aneurysm) (Fig. 2).
FIGURE 2 Axial (a), sagittal (b) and 3D VR TOF (c) images showing an aneurysm of the anterior communicating artery (arrows) displacing and compressing the chiasm. Another aneurysm is evident in the middle cerebral artery (c) (arrowheads).
3 Diffusion imaging
3 DIFFUSION IMAGING Diffusion-weighted imaging estimates the root mean-square displacement due to random Brownian motion of water molecules inside, outside, around, and through cellular structures. Water mobility can be restricted in a number of conditions such as increased cellularity and swelling, whereas, e.g., necrosis is accompanied by an increase of water diffusivity due to the breakdown of cell membranes. The most common approach to diffusion-weighted imaging employs an echo planar pulsed-gradient spin echo sequence with additional diffusion-sensitizing gradients in at least three orthogonal directions (xx, yy, zz). The amount of diffusion weighting can be quantified through the b-value, which includes information about the strength and duration of the applied gradients. In diffusion imaging, a reference image (b-value of 0) is always acquired, after which all spins are dephased and rephased by the application of two strong and opposite gradients of duration d separated by a diffusion time D. Brownian motion between dephasing and rephasing results in incomplete phase recovery and hence signal attenuation with respect to the reference image. Increased diffusion within a tissue will result in a decrease of signal intensity in the diffusion-weighted image, and hence in a higher signal attenuation with respect to the reference image, which would result in a higher estimated apparent diffusion coefficient (ADC). DTI is an extension of conventional diffusion-weighted imaging which has shown great promise in characterizing central nervous system and optic nerve disorders. Through the acquisition of at least six diffusion-weighted images sensitized through noncollinear and noncoplanar gradients, DTI is able to estimate the full diffusion tensor and hence to estimate diffusivities (eigenvalues) along the three principal directions (eigenvectors) within a voxel. The diffusion tensor can be visualized as an ellipsoid, with the three principal axes oriented along the three eigenvectors and whose length corresponds to the three eigenvalues of the diffusion tensor. Accordingly, in an homogeneous isotropic medium, water molecules move freely and randomly in any direction and the diffusion ellipsoid reduces to a sphere. In biological tissue in general and in white matter fiber tracts in particular, water movements are selectively restricted due to microstructural architecture (e.g., water molecules are more likely to diffuse along cellular membranes than across them). In this case, the diffusion-weighted signal is dependent on the relative orientation of the diffusion-sensitizing gradients and the microstructures of the sample, and the diffusion tensor would be represented by an anisotropic displacement probability ellipsoid positioned along the main fiber orientation within the voxel. Accordingly, the orientation of the principal eigenvector is generally assumed to be parallel to the local white matter fascicles in the brain, and voxel-wise directional patterns can be easily visualized using “color maps,” where different colors are assigned to different orientations. The highest eigenvalue represent the diffusivity of water parallel to the axonal fibers and it is commonly referred to as the axial diffusivity (AD), while the other two eigenvalues can be averaged to compute radial (i.e., perpendicular to the axon) diffusivity (RD). The average of the three eigenvalues within a voxel is referred as mean diffusivity (MD) and their sum is
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FIGURE 3 Diffusion tensor images with fiber tracking of the optic nerve (a) and of the visual pathway (b).
the trace of the diffusion tensor, while their normalized variance is commonly termed fractional anisotropy (FA) and is related, among other aspects, to directional coherence of fibers within the voxel. DTI with tractography (Fig. 3) can be employed to study all portions of the visual pathway and will be now discussed in the context of its application within regions between the ON and the OR. A large number of studies have used DTI to describe white matter integrity (Conte et al., 2012; Garaci et al., 2014; Lista et al., 2013; Teipel et al., 2013). Animal studies and postmortem investigations have demonstrated that DTI parameters (increase in MD and reduction of FA) are altered at the level of the ON in optic neuritis (Trip et al., 2006). Hui et al. (2007) have demonstrated the same changes in a rat model of glaucoma. Also, DTI abnormalities have been documented to correlate with cross-sectional area of the prechiasmatic murine optic nerve in a lesional model (Zhang et al., 2011). In our work, we have evaluated relationships
3 Diffusion imaging
between DTI parameters and both glaucoma stages and retinal nerve fiber thickness assessed with scanning laser polarimetry (GDX-VCC), confocal scanning laser ophthalmoscopy (HRT III), and OCT (Bolacchi et al., 2012; Nucci et al., 2012, 2013). We found a progressive increase of MD and decrease of FA according to glaucoma severity, and an increase in MD at the proximal portion of the ON in respect of distal segments in the early stages of the disease suggesting it as an early clue for the diagnosis. In glaucoma patients, Engelhorn et al. (2012a,b) demonstrated a decrease of FA and an increase of RD in the intracranial segment of the optic nerve, while in the intraorbital segment, there was only a slight FA decrease. In a study performed on a 1.5T scanner Zhang et al. (2012) described changes in all DTI parameters in a population of 30 patients affected by NTG with respect to 30 controls. To our knowledge, this was the only study which specifically enrolled NTG patients. The study reported a significant decrease of FA and increase of all diffusivity-related parameters (MD, RD, and AD) which also correlated with the mean perimetric defect. Wang et al. (2013) analyzed a population of patients with closed angle glaucoma and correlated their results with retinal nerve fiber layer (RNFL) thickness evaluated with OCT. Through a region of interest (ROI)-based approach, they documented a significant decrease of FA and an increase in MD, AD, and RD in different segment of the ON (anterior, middle, and posterior). A significant correlation between ROIwise DTI parameters and the RNFL was also demonstrated. In another study, a significant correlation between DTI parameters and HRT II as well as glaucoma severity (evaluated with the Bascom Palmer Glaucoma staging system) was also shown (Chang et al., 2014). Similarly, Sidek et al. correlated DTI-derived parameters obtained on a 3T scanner with RNFL evaluated with OCT and disease severity based on the Hodapp–Anderson–Parrish (HAP) classification (Sidek et al., 2014). While previous studies have confirmed and validated DTI findings on the ON, fewer authors have investigated DTI-related alterations of the OT and LGN. Using the DTI in conjunction with tract-based spatial statistics (TBSS) in 25 patients with POAG, Chen et al. have shown a significant reduction of FA and increase of MD in bilateral OT, which also correlated with glaucoma stage and optic disk damage (Chen et al., 2013a,b). In a similar group of patients, Dai et al. used DTI and whole-brain voxel-wise analysis to demonstrate that FA in the chiasm was significantly lower in glaucoma patients when compared to controls, and that it correlated negatively with the clinical severity (Dai et al., 2013a,b). On the contrary, only a slight FA decrease was documented by Engelhorn in his studies at the level of the chiasm and of the LGN. This nonsignificant alteration was supposed to be due to the high percentage of crossing fibers in both structures, leading to the conclusion that chiasm and the LGN are better evaluated with morphological imaging in conjunction with VBM. The OR have been investigated employing a number of statistical methods and several segmentation strategies. Using a ROI-based approach, we have demonstrated a significant increase of MD and reduction of FA in the OR in 16 patients with POAG (Garaci et al., 2009). Engelhorn et al. were the first to develop a software for
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semiautomated segmentation and quantification of the OR (Engelhorn et al., 2010). Using fiber tracking techniques, they showed a decrease of the 38% of the optical radiation total volume in glaucoma, and successively showed that the total volume loss could reach the 44% and that it was correlated with the severity of the disease. Average rendered volume among glaucoma patient reached the 67% of controls (Engelhorn et al., 2011). Quantification of FA was also conducted at three levels of the OR (directly after the LGN, at the level of the posterior horn of the lateral ventricle, and before its cortical spread) showing a significant decrease associated with RD increase in correlation with the severity of optic nerve atrophy and visual impairment. Similarly, Michelson demonstrated a smaller OR in a POAG patient and found a correlation between FA-, RD-, ADC-, and HRT-based glaucoma indices. These results were followed by the experience of El-Rafei et al., who after designing a DTI-based, automated segmentation strategy to identify the optic radiation (El-Rafei et al., 2011a,b), enrolled 23 subjects with POAG or NTG, and showed diffuse decrease of FA in the glaucoma group and more localized increase of RD and MD when compared to controls. Interestingly, the Meyer loop showed the highest MD and RD values in glaucoma patients (El-Rafei et al., 2011a,b). In POAG, FA reduction has been demonstrated to involve also other WM tracts such as the inferior fronto-occipital fasciculus, the longitudinal and inferior frontal fasciculi, the caudate nucleus, the putamen, the thalamic radiation, and the anterior and posterior limb of the internal capsule (Zikou et al., 2012). Dai et al. (2013a,b) found that RD of the OR was significantly higher in glaucoma patients than in controls, and that those indexes were positively correlated with clinical stage. Surprisingly, no significant groupwise differences of AD, MD, or FA and no correlation between OR parameters and RNFL were found. However, Chen et al. (2013a,b) used TBSS to show a significant FA decrease and MD increase in the OR. Only FA in the OR was found to correlate with disease stage. The TBSS approach was also employed by Lu et al. in a POAG patient population, showing a significant decrease of FA in the OR of glaucoma patients as compared to controls (Lu et al., 2013). A decrease of FA in the OR which correlated with clinical parameters was also observed by Murai et al. (2013). Recently, Kaushik et al. have used DTI-based tractography to examine OR bundles, also evaluating DTI parameters in two groups of POAG patients which differed in terms of hemifield defect along with a control group. A lower number of bundles were found in both glaucoma groups as compared to controls, and the comparison of DTI parameter showed a FA significant reduction and increase of RD (Kaushik et al., 2014). Evidence from previous studies was collected by the El-Rafei group, which proposed to use a visual pathway analysis based on the DTI segmentation of OR and extraction of features describing the state of its fiber bundles to classify glaucoma patients. This process led to a correct separation of glaucoma patients from normal controls with an accuracy of 92.4%. Also, POAG patients were distinguished from a NTG population with an accuracy of 98.3% (El-Rafei et al., 2013). Also, DTI-related parameters (and FA, in particular) have been shown by Schoemann et al. to correlate with the presence and the entity of white matter lesions in the OR (Schoemann et al., 2014).
4 Functional imaging
4 FUNCTIONAL IMAGING Functional MRI (fMRI) plays a pivotal role in inferring neuronal activity. Compared with positron emission tomography (PET) and single-photon emission computed tomography, this noninvasive imaging technique allows to image response localization following various stimuli with an intrinsically higher spatial resolution and without the need for radioisotope administration. Functional imaging comprises two different MR techniques: blood oxygen level-dependent (BOLD) imaging and arterial spin labeling (ASL) imaging. BOLD imaging is based on the observation of changes in local hemodynamics following neural activity. Changes in blood oxygenation affect the MR signal due to variations in concentration of deoxyhemoglobin, which is a paramagnetic agent. Increased neural activity is followed by upregulation of local blood flow leading to a reduction of relative deoxyhemoglobin concentration at the venular bed, which can be detected using MRI. ASL is based on the effect of the exchange between previously magnetically labeled blood water and the blood water of the ROI. Arterial water is labeled below the ROI with a 180° inversion pulse. The obtained inverted spins which then inflow within the tissue of interest alter the total magnetization determining an MR signal reduction. The use of ASL instead of BOLD has been previously demonstrated to lead to a better activation localization because it focuses prominently on the capillary rather than the venular vascular bed (Duong et al., 2002). The BOLD technique can easily demonstrate visual cortex activation during a stimulation as shown by Logothetis et al. in monkeys (Logothetis et al., 2001). Neural response to a visual stimulus begins within a few hundreds of milliseconds. The reduction of signal intensity, which is the source of BOLD signal, is observed 0.5–2.0 s after the stimulus onset. Visual cortex and striate and extrastriate areas activation was firstly demonstrated by Courtney et al. and Engel et al. exposing the subjects to an expandingcontracting ring stimuli which was known to generate a strong neural response in V1 (Courtney and Ungerleider, 1997; Engel et al., 1997). Following these first experiences, great effort was made to demonstrate the correlation between BOLD– fMRI and traditional visual examination in several pathologic conditions such as hemianopia due to prechiasmatic, chiasmatic and retrochiasmatic lesions, optic neuritis, and space occupying lesions of the optic radiation (Miki et al., 1996). Pathologic activation patterns were also observed in patients affected by dyslexia and in schizophrenics who experienced visual hallucinations (Oertel et al., 2007). BOLD–fMRI can be used to evaluate neural response after a visual stimulus or regional interactions that occur when a subject is not performing an explicit task. The latter is known as resting state fMRI (rsfMRI) and has allowed to demonstrate the existence of several subnetworks of areas which are functionally connected at rest. Based on the experience gained in optic neuropathy, in which the stimulation of the affected eye failed to activate V1 areas corresponding to the central visual field defects (Gareau et al., 1999), Duncan et al. (2007) demonstrated that viewing with the fellow (nonglaucomatous) eye elicited a greater fMRI response in V1 in POAG patients when compared to controls. Additionally, there was a significant agreement
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between the pattern of visual loss and the pattern of BOLD activity in the cortex, and a significant correlation between changes in BOLD response and difference in sensitivity thresholds between the glaucomatous and fellow eye (PDdif ) obtained with standard automated perimetry (Duncan et al., 2007, 2012). Later Qing et al. evaluated POAG patients with spared central vision in a task induced experiment. They found that the cortical response to a checkerboard stimulus presented at the apparently normal central visual field in the glaucomatous eye elicited a less prominent BOLD signal in the visual cortex than if presented at the fellow eye. This was suggested to correlate with daily difficulties in visual tasks which are only partially predicted by the overall visual loss (Qing et al., 2010). Following these task-based BOLD studies, additional attention has been devoted to functional connectivity (FC) and resting state alterations in glaucoma patients. Wang et al. were the first to demonstrate a nonrandom spontaneous activity within the primary visual cortex of normal individuals. They showed a network of brain areas functionally connected with the visual cortex such as visual association areas, the precuneus, the precentral/ postcentral gyrus, the middle frontal gyrus, the fusiform gyrus, the inferior/middle temporal gyrus, and the parahippocampal gyrus (Wang et al., 2008). Dai et al. showed significant differences in activation of functionally connected areas in glaucoma patients as compared to controls. In particular, the activity in the right inferior temporal gyrus (BA37), left middle occipital gyrus (BA19), left postcentral gyrus (BA4), and right superior occipital gyrus (BA19) was decreased in POAG patients. A decrease in positive FC between primary visual cortex and higher cortices suggested a lesser incorporation of visual information with other stimuli leading to diminished integration with language/working memory or sensorimotor information. When comparing these patients to controls, negative FC was demonstrated to disappear between BA17 with the extranuclear regions (BA25), the right temporal, right middle frontal gyrus (BA10), right middle cerebellar peduncle, left cerebellum, and right insular gyrus. This phenomenon could be due to compensation-related recruitment of new areas, as it was previously demonstrated in other neurodegenerative diseases (Dai et al., 2013a,b). Recently, Frezzotti et al. (2014) demonstrated an altered FC in five of eight resting state networks in patients with advanced glaucoma. In particular, a lower FC was found in the working memory network including the superior frontal gyrus (SFG) on the left and the supramarginal gyrus and lateral occipital cortex on the right, in the extrastriate region of the visual network including the right lingual gyrus, and in the dorsal attention network including the lateral occipital cortex bilaterally and pre- and postcentral gyrus on the left. A higher FC was found in the visual network including lateral occipital cortex bilaterally and temporo-occipital fusiform cortex and in the medial part of the executive network including SFG, paracingulate, and anterior cingulate gyrus (Frezzotti et al., 2014). Interestingly, they found an increase of FC with the higher cortices (secondary visual cortex) suggesting a reduction of inhibitory signals from the primary cortex. Altered spontaneous brain activity was also documented by Song et al. who conducted a rsfMRI study in POAG patients. They performed a regional homogeneity (ReHo) analysis based on rsfMRI data. When compared to controls, ReHo values in POAG patients were significantly increased in the right dorsal anterior cingulated cortex, in the bilateral medial fontal
5 Voxel-based morphometry
gyrus and in the right cerebellar anterior lobe and significantly decreased in the bilateral calcarine, bilateral precuneus, bilateral precentral/postcentral gyrus, left inferior parietal lobule, and left cerebellar posterior lobe. A negative correlation between the spontaneous activity of the precuneus and clinical severity was also demonstrated (Song et al., 2014). Liu et al. explored the distribution between abnormal regional intrinsic activities in the glaucomatous brain and their correlation with disease severity. They performed a rsfMRI study on POAG patients measuring the amplitude of low frequency fluctuations (ALFF) in the BOLD signal. Patients showed an ALFF value increase in the right medial frontal gyrus and superior motor area, while a decrease was noted in the right occipital lingual gyrus, right inferior temporal gyrus, and left precentral gyrus when compared to controls. Correlation analysis with the HAP score showed that the ALFF was positively and negatively correlated with the right SFG and the right precentral gyrus on one hand, and the left occipital lobe and left precentral gyrus on the other hand, respectively (Liu and Tian, 2014). Similarly, Li et al. showed decreased ALFF values in the visual cortices, in the posterior default network and in the motor and sensory cortices of glaucoma patients with respect to controls. Increased ALFF values were detected in the prefrontal cortex, left superior temporal gyrus, right middle cingulate cortex, and left inferior parietal lobule. A positive correlation was found between HAP score and ALFF values in the right SFG, while a negative correlation was found with the cuneus. In POAG patients, the HAP score for POAG was positively correlated with ALFF values of the right SFG and negatively correlated with ALFF values of the left cuneus (Li et al., 2015). To our knowledge, there is only one report on the use of ASL fMRI to evaluate cerebral blood flow (CBF) in V1 in glaucoma patients. Ten POAG patients were recruited by Duncan et al., who performed ASL on a 3T MR scanner. CBF resulted significantly lower for regions belonging to the primary visual cortex that corresponded to glaucomatous region of the visual field (Duncan et al., 2012).
5 VOXEL-BASED MORPHOMETRY VBM is a structural processing technique based on the statistical parametric mapping that allows the investigation of focal differences in brain anatomy. It involves a voxel-wise comparison of the local concentration of gray matter (GM) between groups of subjects. The brain images are registered to a template and smoothed so that each voxel represents the average of itself and its neighbors. After modulation of the image by the Jacobian determinant of the resulting warp, local volume is compared across the brain on a voxel basis. There are several studies in which VBM was used to identify volume changes of the visual system GM in glaucoma patients. The majority of these studies showed a decrease GM volume in the occipital and other cortices and in other brain regions such as ON, chiasma, OT, LGN, and OR (Boucard et al., 2009; Hernowo et al., 2011; Zikou et al., 2012). In contrast, Li et al. identified an increase of GM density in the region adjacent to BA39 and, by Chen et al., who demonstrated an increase of GM volume in several locations such as middle temporal gyrus, inferior parietal gyrus, angular gyrus, left superior parietal gyrus, left
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precuneus, and left middle occipital gyrus (Chen et al., 2013a,b; Li et al., 2012). Recently, Bogorodzky et al. described significant cortical thinning around the calcarine sulci (BA17, BA18), in the left middle temporal gyrus and in the fusiform gyrus (BA19) bilaterally and Frezzotti et al., using a VBM style approach, identified regions of GM atrophy in the hippocampus, fronto-orbital cortex, and superior parietal lobule in POAG patients (Bogorodzki et al., 2014; Frezzotti et al., 2014). All these papers on VBM focused only on advanced stage POAG patients or failed to demonstrate GM alterations in the early stages. Recently, William et al. found that 20% of brain structures in POAG patients were larger (in terms of absolute volume) than in controls (right and left inferior occipital gyri and the right middle occipital gyrus, right inferior temporal gyrus, and right occipital lobe white matter), while when analyzing only moderate/advanced stage patients three structures were larger (left inferior occipital gyrus, right middle occipital gyrus, and right superior occipital gyrus) and two smaller (right SFG and corpus callosum) when compared to control (Williams et al., 2013). Similarly, Yu et al. demonstrated a reduction of cortical thickness at the level of V5/MT in mild POAG patients and in anterior V1, V2, and V5/MT in severe glaucomatous patients. Clinical data were shown to significantly correlate with the V5/MT and posterior V2 cortical thickness (Yu et al., 2014). To our knowledge, there are no data in literature focusing on the usefulness of VBM in non-POAG glaucoma patients, however, it appears likely that VBM could be used as an effective tool to demonstrate visual pathway atrophy and compensative regional recruitment in all glaucoma patients.
6 MAGNETIC RESONANCE SPECTROSCOPY Magnetic resonance spectroscopy (MRS) is a noninvasive technique that allows the selective study of metabolite concentration in tissues. The most common strategy is to obtain proton spectra, and the relatively low incidence of motion artifacts (with respect to other body segments) make the brain a suitable organ for MRS imaging. At least three peaks can be identified in the proton MR spectrum: Creatine and Phosphocreatine (Cr), Choline (Cho), and N-acetyl-aspartate (NAA). They represent markers of cellular energy storage, of cytosolic choline compounds such as phosphocholine, glycerophosphocholine, acetylcholine, and others, and of neuronal cellular integrity, respectively. Boucard was the first to analyze proton spectra in age-related macular degeneration and glaucomatous patient along with a control population in a study based on the single voxel MRS of the occipital cortex. His results failed to show any significant difference between patient group and controls in the amount of NAA, Cho, and Cr (Boucard et al., 2007). Additional interest in MRS in glaucoma was generated by the results of a study on a rat model of glaucoma which documented a significant decrease of Cho/Cr ratio in the visual cortex (Chan et al., 2009). In agreement with previous results on humans, Doganay et al. did not find any significant variation in main metabolites but identified a significant increase of glutamine + glutamate (Glx)/Cr ratio, both in the vitreous and in the LGN. This is in accordance with the
References
hypothesis that excitotoxicity is involved in the mechanisms of neuronal damage in glaucoma (Doganay et al., 2012). Recently, Zhang et al. used multivoxel spectroscopy to analyze metabolites in the LGN and in the visual cortex. Their study included both POAG and primary closed angle glaucoma patients examined on a 3T scanner. In this study, no group-wise differences were found in the Glx/Cr ratio; however, a statistically significant difference was documented in NAA/Cr and Cho/Cr in the geniculocalcarine structures. To our knowledge, this is the only study to show reduction of NAA and Cho in humans, possibly in accordance with the idea of cell apoptosis in the striate areas of glaucoma patients (Zhang et al., 2013). Further research is needed to unify the currently partially contrasting findings in the literature. In this context, multivoxel MRS could aid in detecting the small and widespread metabolites alteration within the visual cortex and visual pathway in glaucomatous patients.
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Conte, A., Brancati, F., Garaci, F., Toschi, N., Bologna, M., Fabbrini, G., Falla, M., Dallapiccola, B., Bollero, P., Floris, R., Berardelli, A., 2012. Kinematic and diffusion tensor imaging definition of familial Marcus Gunn jaw-winking synkinesis. PLoS One 7 (12), e51749. Courtney, S.M., Ungerleider, L.G., 1997. What fMRI has taught us about human vision. Curr. Opin. Neurobiol. 7 (4), 554–561. Dai, H., Morelli, J.N., Ai, F., Yin, D., Hu, C., Xu, D., Li, Y., 2013a. Resting-state functional MRI: functional connectivity analysis of the visual cortex in primary open-angle glaucoma patients. Hum. Brain Mapp. 34 (10), 2455–2463. Dai, H., Yin, D., Hu, C., Morelli, J.N., Hu, S., Yan, X., Xu, D., 2013b. Whole-brain voxelbased analysis of diffusion tensor MRI parameters in patients with primary open angle glaucoma and correlation with clinical glaucoma stage. Neuroradiology 55 (2), 233–243. Doganay, S., Cankaya, C., Alkan, A., 2012. Evaluation of corpus geniculatum laterale and vitreous fluid by magnetic resonance spectroscopy in patients with glaucoma; a preliminary study. Eye (Lond.) 26 (8), 1044–1051. Duncan, R.O., Sample, P.A., Weinreb, R.N., Bowd, C., Zangwill, L.M., 2007. Retinotopic organization of primary visual cortex in glaucoma: comparing fMRI measurements of cortical function with visual field loss. Prog. Retin. Eye Res. 26 (1), 38–56. Duncan, R.O., Sample, P.A., Bowd, C., Weinreb, R.N., Zangwill, L.M., 2012. Arterial spin labeling fMRI measurements of decreased blood flow in primary visual cortex correlates with decreased visual function in human glaucoma. Vision Res. 60, 51–60. Duong, T.Q., Yacoub, E., Adriany, G., Hu, X., Ugurbil, K., Vaughan, J.T., Merkle, H., Kim, S.G., 2002. High-resolution, spin-echo BOLD, and CBF fMRI at 4 and 7 T. Magn. Reson. Med. 48 (4), 589–593. El-Rafei, A., Engelhorn, T., Waerntges, S., Doerfler, A., Hornegger, J., Michelson, G., 2011a. Automatic segmentation of the optic radiation using DTI in healthy subjects and patients with glaucoma. In: Tavares, J.M.R.S., Jorge, R.M.N. (Eds.), Computational Vision and Medical Image Processing. vol. 19. Springer, Netherlands, pp. 1–15. El-Rafei, A., Engelhorn, T., Warntges, S., Dorfler, A., Hornegger, J., Michelson, G., 2011b. A framework for voxel-based morphometric analysis of the optic radiation using diffusion tensor imaging in glaucoma. Magn. Reson. Imaging 29 (8), 1076–1087. El-Rafei, A., Engelhorn, T., Warntges, S., Dorfler, A., Hornegger, J., Michelson, G., 2013. Glaucoma classification based on visual pathway analysis using diffusion tensor imaging. Magn. Reson. Imaging 31 (7), 1081–1091. Engel, S.A., Glover, G.H., Wandell, B.A., 1997. Retinotopic organization in human visual cortex and the spatial precision of functional MRI. Cereb. Cortex 7 (2), 181–192. Engelhorn, T., Haider, S., Michelson, G., Doerfler, A., 2010. A new semi-quantitative approach for analysing 3 T diffusion tensor imaging of optic fibres and its clinical evaluation in glaucoma. Acad. Radiol. 17 (10), 1313–1316. Engelhorn, T., Michelson, G., Waerntges, S., Struffert, T., Haider, S., Doerfler, A., 2011. Diffusion tensor imaging detects rarefaction of optic radiation in glaucoma patients. Acad. Radiol. 18 (6), 764–769. Engelhorn, T., Michelson, G., Waerntges, S., Hempel, S., El-Rafei, A., Struffert, T., Doerfler, A., 2012a. A new approach to assess intracranial white matter abnormalities in glaucoma patients: changes of fractional anisotropy detected by 3 T diffusion tensor imaging. Acad. Radiol. 19 (4), 485–488. Engelhorn, T., Michelson, G., Waerntges, S., Otto, M., El-Rafei, A., Struffert, T., Doerfler, A., 2012b. Changes of radial diffusivity and fractional anisotropy in the optic nerve and optic radiation of glaucoma patients. ScientificWorldJournal 2012, 849632.
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Miki, A., Nakajima, T., Fujita, M., Takagi, M., Abe, H., 1996. Functional magnetic resonance imaging in homonymous hemianopsia. Am. J. Ophthalmol. 121 (3), 258–266. Murai, H., Suzuki, Y., Kiyosawa, M., Tokumaru, A.M., Ishii, K., Mochizuki, M., 2013. Positive correlation between the degree of visual field defect and optic radiation damage in glaucoma patients. Jpn. J. Ophthalmol. 57 (3), 257–262. Nucci, C., Mancino, R., Martucci, A., Bolacchi, F., Manenti, G., Cedrone, C., Culasso, F., Floris, R., Cerulli, L., Garaci, F.G., 2012. 3-T Diffusion tensor imaging of the optic nerve in subjects with glaucoma: correlation with GDx-VCC, HRT-III and Stratus optical coherence tomography findings. Br. J. Ophthalmol. 96 (7), 976–980. Nucci, C., Martucci, A., Cesareo, M., Mancino, R., Russo, R., Bagetta, G., Cerulli, L., Garaci, F.G., 2013. Brain involvement in glaucoma: advanced neuroimaging for understanding and monitoring a new target for therapy. Curr. Opin. Pharmacol. 13 (1), 128–133. Oertel, V., Rotarska-Jagiela, A., van de Ven, V.G., Haenschel, C., Maurer, K., Linden, D.E., 2007. Visual hallucinations in schizophrenia investigated with functional magnetic resonance imaging. Psychiatry Res. 156 (3), 269–273. Qing, G., Zhang, S., Wang, B., Wang, N., 2010. Functional MRI signal changes in primary visual cortex corresponding to the central normal visual field of patients with primary open-angle glaucoma. Invest. Ophthalmol. Vis. Sci. 51 (9), 4627–4634. Schoemann, J., Engelhorn, T., Waerntges, S., Doerfler, A., El-Rafei, A., Michelson, G., 2014. Cerebral microinfarcts in primary open-angle glaucoma correlated with DTI-derived integrity of optic radiation. Invest. Ophthalmol. Vis. Sci. 55 (11), 7241–7247. Sidek, S., Ramli, N., Rahmat, K., Ramli, N.M., Abdulrahman, F., Tan, L.K., 2014. Glaucoma severity affects diffusion tensor imaging (DTI) parameters of the optic nerve and optic radiation. Eur. J. Radiol. 83 (8), 1437–1441. Song, Y., Mu, K., Wang, J., Lin, F., Chen, Z., Yan, X., Hao, Y., Zhu, W., Zhang, H., 2014. Altered spontaneous brain activity in primary open angle glaucoma: a resting-state functional magnetic resonance imaging study. PLoS One 9 (2), e89493. Teipel, S.J., Grothe, M., Lista, S., Toschi, N., Garaci, F.G., Hampel, H., 2013. Relevance of magnetic resonance imaging for early detection and diagnosis of Alzheimer disease. Med. Clin. North Am. 97 (3), 399–424. Trip, S.A., Wheeler-Kingshott, C., Jones, S.J., Li, W.Y., Barker, G.J., Thompson, A.J., Plant, G.T., Miller, D.H., 2006. Optic nerve diffusion tensor imaging in optic neuritis. Neuroimage 30 (2), 498–505. Wang, K., Jiang, T., Yu, C., Tian, L., Li, J., Liu, Y., Zhou, Y., Xu, L., Song, M., Li, K., 2008. Spontaneous activity associated with primary visual cortex: a resting-state FMRI study. Cereb. Cortex 18 (3), 697–704. Wang, M.Y., Wu, K., Xu, J.M., Dai, J., Qin, W., Liu, J., Tian, J., Shi, D., 2013. Quantitative 3-T diffusion tensor imaging in detecting optic nerve degeneration in patients with glaucoma: association with retinal nerve fiber layer thickness and clinical severity. Neuroradiology 55 (4), 493–498. Williams, A.L., Lackey, J., Wizov, S.S., Chia, T.M., Gatla, S., Moster, M.L., Sergott, R., Spaeth, G.L., Lai, S., 2013. Evidence for widespread structural brain changes in glaucoma: a preliminary voxel-based MRI study. Invest. Ophthalmol. Vis. Sci. 54 (8), 5880–5887. Yu, L., Yin, X., Dai, C., Liang, M., Wei, L., Li, C., Zhang, J., Xie, B., Wang, J., 2014. Morphologic changes in the anterior and posterior subregions of V1 and V2 and the V5/MT + in patients with primary open-angle glaucoma. Brain Res. 1588, 135–143. Zhang, X., Sun, P., Wang, J., Wang, Q., Song, S.K., 2011. Diffusion tensor imaging detects retinal ganglion cell axon damage in the mouse model of optic nerve crush. Invest. Ophthalmol. Vis. Sci. 52 (9), 7001–7006.
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8
Francesco Garaci*,1, Simone Altobelli†, Nicola Toschi{,}, Raffaele Mancino}, Carlo Nucci}, Orazio Schillaci{,k, Roberto Floris†,{ *Diagnostic Imaging Section, Tor Vergata University Hospital, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy † Diagnostic Imaging section, Tor Vergata University Hospital, University of Rome Tor Vergata, Rome, Italy { Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy } Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging and Harvard Medical School, Boston, MA, USA } Ophthalmology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy k IRCCS Neuromed, Pozzilli, Italy 1 Corresponding author: Tel.: +39-06-20902471; Fax: +39-06-20902471, e-mail address: [email protected]
Abstract Recent advances in Magnetic Resonance Imaging (MRI) technology have brought new insight in central nervous system (CNS) manifestation of glaucoma. New MR techniques allowed to identify in vivo and noninvasively alterations along all the visual pathway in both early and late stages of the disease. Conventional neuroimaging still plays an important role, mostly in the anatomy description and in the differential diagnosis with space occupying lesions but it should be supported by other advanced MR techniques such as diffusion tensor imaging, functional imaging (BOLD–ASL), and magnetic resonance spectroscopy, which offer the possibility to investigate deep white matter tracts integrity and cortical gray matter changes. In a future perspective, MR quantification of CNS damage associated with glaucoma will be of pivotal importance for prognostic stratification and evaluation of neuroprotective therapy response.
Keywords MR imaging, Diffusion tensor imaging, Glaucoma, MR spectroscopy, fMRI
Progress in Brain Research, Volume 221, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2015.06.004 © 2015 Elsevier B.V. All rights reserved.
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1 BACKGROUND Although one of the most important and well-known risk factor for glaucoma is increased intraocular pressure (IOP) (>21 mmHG), some patients present with normal IOP (often termed “normal pressure” or “normal tension” glaucoma). Further, in spite of regular IOP drug monitoring, a number of glaucomatous patients demonstrate a progression of both retinal ganglion cell and optic nerve degeneration. These aspects of glaucoma have suggested that the pathogenesis of the disease might be more complex than previously hypothesized. In this context, the manifestations of glaucoma (or at least of some subgroups) are not limited to the ocular bulbs but rather involve all optic pathways from bulb to cortex, hence including the brain. The first ex vivo data documenting human brain involvement in glaucoma have been published by Gupta et al. (Gupta and Yucel, 2006): in this important study, histopathology demonstrated a significant volume reduction of both the lateral geniculate nucleus (LGN) and the visual cortex as compared to controls. Successively, neuroimaging has been able to demonstrate that this “damage” can be quantified, in vivo and noninvasively, in all optic pathways (Garaci et al., 2009), opening an extraordinary and challenging field of research which has rapidly developed in the last 5–8 years. In this context, magnetic resonance imaging (MRI) was demonstrated to be the method of choice due to its ability to visualize the optic nerve and chiasm noninvasively and with excellent contrast; deep visual pathways can also be assessed with advanced MR techniques such as diffusion tensor imaging (DTI), functional imaging (BOLD–ASL), and spectroscopy. The purpose of this chapter is to critically review the literature documenting the use of MRI to evaluate glaucoma neuropathy. Current applied techniques and published results are discussed along with future perspectives and potential prospective applications in neuroprotective drug monitoring.
2 CONVENTIONAL MRI MRI allows rapid assessment of visual system anatomy including orbital structures such as the globe, the optic nerve and canal, retrobulbar adipose tissue, orbital muscles, and the apex (Fig. 1). Deeper structures like the chiasm and the optic tract can be also imaged accurately through morphological MR sequences. The rest of the visual pathway is more challenging to distinguish in conventional imaging and usually requires more advances techniques. Anatomical imaging is based on the tissuedependent differences in MR signal, which allow to distinguish, e.g., white or gray matter and cerebrospinal fluid (CSF). Morphologic sequences are conventionally employed as a first step to identify space occupying lesions or other pathologic processes of the visual system. The optic nerve is sheathed with leptomeninges and has a subarachnoidal space of 0.4–0.6 mm which is directly connected with its corresponding intracranial space. Its overall length is 50 mm and it can be divided in four segments: the intraocular
2 Conventional MRI
FIGURE 1 Axial T1 weighted images documenting the optic nerve segments and the orbital muscular cone anatomy.
(1 mm), intraorbital (25–30 mm), intracanalicular (6 mm), and intracranial segments (5–16 mm). The intraorbital segment is easily identifiable in MR images due to the contrast between nerve tissue and the surrounding adipose tissue of the orbit. In this context, T1-weighted 3D inversion recovery (IR) sequences are extremely useful because of their high signal-to-noise ratio and the possibility to reslice in all orthogonal planes. In general, macroscopical anatomy is best assessed using T1-weighted techniques (usually integrated with fat suppression techniques), in particular after Gadolinium administration which allows better visualization of contrast-enhanced intraorbital masses. T2-weighted sequences, in particular on the axial and coronal planes, are useful to visualize space occupying lesion or optic nerve atrophy. Glaucoma causes a loss of neural fibers within the optic nerve leading to a decrease of its size which is more pronounced at its distal level. Normal thickness values of the intraorbital segment of the ON range from 3.1 mm (anterior) to 2.5 mm (posterior), whereas the mean dural diameter ranges between 5.1 (anterior) and 2.8 (posterior). Thinning of the nerve and widening of its subarachnoidal space has been described in previous studies and has been correlated with the thickness of the nerve fiber layers using optical coherence tomography (OCT). For instance, Lagreze et al. (2009) used a HASTE ultrafast sequence on a 3T scanner documenting a significant correlation between ON diameter and OCT results. Similarly, Kashiwagi et al. (2004) documented that the optic nerve diameter was significantly smaller in glaucoma patients (2.25 0.33 mm) when compared to controls (2.47 0.24 mm). The chiasm and the optic tract are best identified with T1-weighted images, as demonstrated previously in Kashiwagi’s work was documented a reduction of the height of the optic chiasm in glaucoma patients (2.12 0.37 mm) compared with controls (2.77 0.36 mm) (Kashiwagi et al., 2004). The optic chiasm is clearly visible in T2-weighted images because it is surrounded by CSF in the chiasmatic cistern.
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Optical tract fibers close to the LGN as well as the LGN itself, where the third neuron of the visual pathway is located, are difficult to visualize in conventional MRI and their anatomy and pathology can only be evaluated approximately with T1-weighted IR sequences. Postgeniculate fibers and the optic radiation cannot be imaged with conventional morphological sequences ( Jacobs and Galetta, 2007); thus, more advances morphological processing techniques such as voxel-based morphometry (VBM) or diffusion-based imaging techniques such as DTI are necessary. Also, the overall contrast between gray and white matter allows the visual cortex to be distinguished on conventional imaging, however, its function and detailed anatomy is better described by advanced techniques. Lastly, the use of Gadolinium-enhanced T1 images is mandatory if inflammatory or neoplastic diseases are suspected across the whole visual system. In the context of contrast-enhanced imaging, new insights are likely to be provided by the use in humans of new manganese-based contrast agents which have been seen to clearly enhance the visualization of glaucoma-related changes in animals (Calkins et al., 2008). Angio-MRI of Willis circle, using the time of flight (TOF) technique without the administration of contrast material, is also needed to rule out extrinsic compression of the optic pathways (usually at the level of optic chiasm) by vascular malformations (e.g., aneurysm) (Fig. 2).
FIGURE 2 Axial (a), sagittal (b) and 3D VR TOF (c) images showing an aneurysm of the anterior communicating artery (arrows) displacing and compressing the chiasm. Another aneurysm is evident in the middle cerebral artery (c) (arrowheads).
3 Diffusion imaging
3 DIFFUSION IMAGING Diffusion-weighted imaging estimates the root mean-square displacement due to random Brownian motion of water molecules inside, outside, around, and through cellular structures. Water mobility can be restricted in a number of conditions such as increased cellularity and swelling, whereas, e.g., necrosis is accompanied by an increase of water diffusivity due to the breakdown of cell membranes. The most common approach to diffusion-weighted imaging employs an echo planar pulsed-gradient spin echo sequence with additional diffusion-sensitizing gradients in at least three orthogonal directions (xx, yy, zz). The amount of diffusion weighting can be quantified through the b-value, which includes information about the strength and duration of the applied gradients. In diffusion imaging, a reference image (b-value of 0) is always acquired, after which all spins are dephased and rephased by the application of two strong and opposite gradients of duration d separated by a diffusion time D. Brownian motion between dephasing and rephasing results in incomplete phase recovery and hence signal attenuation with respect to the reference image. Increased diffusion within a tissue will result in a decrease of signal intensity in the diffusion-weighted image, and hence in a higher signal attenuation with respect to the reference image, which would result in a higher estimated apparent diffusion coefficient (ADC). DTI is an extension of conventional diffusion-weighted imaging which has shown great promise in characterizing central nervous system and optic nerve disorders. Through the acquisition of at least six diffusion-weighted images sensitized through noncollinear and noncoplanar gradients, DTI is able to estimate the full diffusion tensor and hence to estimate diffusivities (eigenvalues) along the three principal directions (eigenvectors) within a voxel. The diffusion tensor can be visualized as an ellipsoid, with the three principal axes oriented along the three eigenvectors and whose length corresponds to the three eigenvalues of the diffusion tensor. Accordingly, in an homogeneous isotropic medium, water molecules move freely and randomly in any direction and the diffusion ellipsoid reduces to a sphere. In biological tissue in general and in white matter fiber tracts in particular, water movements are selectively restricted due to microstructural architecture (e.g., water molecules are more likely to diffuse along cellular membranes than across them). In this case, the diffusion-weighted signal is dependent on the relative orientation of the diffusion-sensitizing gradients and the microstructures of the sample, and the diffusion tensor would be represented by an anisotropic displacement probability ellipsoid positioned along the main fiber orientation within the voxel. Accordingly, the orientation of the principal eigenvector is generally assumed to be parallel to the local white matter fascicles in the brain, and voxel-wise directional patterns can be easily visualized using “color maps,” where different colors are assigned to different orientations. The highest eigenvalue represent the diffusivity of water parallel to the axonal fibers and it is commonly referred to as the axial diffusivity (AD), while the other two eigenvalues can be averaged to compute radial (i.e., perpendicular to the axon) diffusivity (RD). The average of the three eigenvalues within a voxel is referred as mean diffusivity (MD) and their sum is
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FIGURE 3 Diffusion tensor images with fiber tracking of the optic nerve (a) and of the visual pathway (b).
the trace of the diffusion tensor, while their normalized variance is commonly termed fractional anisotropy (FA) and is related, among other aspects, to directional coherence of fibers within the voxel. DTI with tractography (Fig. 3) can be employed to study all portions of the visual pathway and will be now discussed in the context of its application within regions between the ON and the OR. A large number of studies have used DTI to describe white matter integrity (Conte et al., 2012; Garaci et al., 2014; Lista et al., 2013; Teipel et al., 2013). Animal studies and postmortem investigations have demonstrated that DTI parameters (increase in MD and reduction of FA) are altered at the level of the ON in optic neuritis (Trip et al., 2006). Hui et al. (2007) have demonstrated the same changes in a rat model of glaucoma. Also, DTI abnormalities have been documented to correlate with cross-sectional area of the prechiasmatic murine optic nerve in a lesional model (Zhang et al., 2011). In our work, we have evaluated relationships
3 Diffusion imaging
between DTI parameters and both glaucoma stages and retinal nerve fiber thickness assessed with scanning laser polarimetry (GDX-VCC), confocal scanning laser ophthalmoscopy (HRT III), and OCT (Bolacchi et al., 2012; Nucci et al., 2012, 2013). We found a progressive increase of MD and decrease of FA according to glaucoma severity, and an increase in MD at the proximal portion of the ON in respect of distal segments in the early stages of the disease suggesting it as an early clue for the diagnosis. In glaucoma patients, Engelhorn et al. (2012a,b) demonstrated a decrease of FA and an increase of RD in the intracranial segment of the optic nerve, while in the intraorbital segment, there was only a slight FA decrease. In a study performed on a 1.5T scanner Zhang et al. (2012) described changes in all DTI parameters in a population of 30 patients affected by NTG with respect to 30 controls. To our knowledge, this was the only study which specifically enrolled NTG patients. The study reported a significant decrease of FA and increase of all diffusivity-related parameters (MD, RD, and AD) which also correlated with the mean perimetric defect. Wang et al. (2013) analyzed a population of patients with closed angle glaucoma and correlated their results with retinal nerve fiber layer (RNFL) thickness evaluated with OCT. Through a region of interest (ROI)-based approach, they documented a significant decrease of FA and an increase in MD, AD, and RD in different segment of the ON (anterior, middle, and posterior). A significant correlation between ROIwise DTI parameters and the RNFL was also demonstrated. In another study, a significant correlation between DTI parameters and HRT II as well as glaucoma severity (evaluated with the Bascom Palmer Glaucoma staging system) was also shown (Chang et al., 2014). Similarly, Sidek et al. correlated DTI-derived parameters obtained on a 3T scanner with RNFL evaluated with OCT and disease severity based on the Hodapp–Anderson–Parrish (HAP) classification (Sidek et al., 2014). While previous studies have confirmed and validated DTI findings on the ON, fewer authors have investigated DTI-related alterations of the OT and LGN. Using the DTI in conjunction with tract-based spatial statistics (TBSS) in 25 patients with POAG, Chen et al. have shown a significant reduction of FA and increase of MD in bilateral OT, which also correlated with glaucoma stage and optic disk damage (Chen et al., 2013a,b). In a similar group of patients, Dai et al. used DTI and whole-brain voxel-wise analysis to demonstrate that FA in the chiasm was significantly lower in glaucoma patients when compared to controls, and that it correlated negatively with the clinical severity (Dai et al., 2013a,b). On the contrary, only a slight FA decrease was documented by Engelhorn in his studies at the level of the chiasm and of the LGN. This nonsignificant alteration was supposed to be due to the high percentage of crossing fibers in both structures, leading to the conclusion that chiasm and the LGN are better evaluated with morphological imaging in conjunction with VBM. The OR have been investigated employing a number of statistical methods and several segmentation strategies. Using a ROI-based approach, we have demonstrated a significant increase of MD and reduction of FA in the OR in 16 patients with POAG (Garaci et al., 2009). Engelhorn et al. were the first to develop a software for
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semiautomated segmentation and quantification of the OR (Engelhorn et al., 2010). Using fiber tracking techniques, they showed a decrease of the 38% of the optical radiation total volume in glaucoma, and successively showed that the total volume loss could reach the 44% and that it was correlated with the severity of the disease. Average rendered volume among glaucoma patient reached the 67% of controls (Engelhorn et al., 2011). Quantification of FA was also conducted at three levels of the OR (directly after the LGN, at the level of the posterior horn of the lateral ventricle, and before its cortical spread) showing a significant decrease associated with RD increase in correlation with the severity of optic nerve atrophy and visual impairment. Similarly, Michelson demonstrated a smaller OR in a POAG patient and found a correlation between FA-, RD-, ADC-, and HRT-based glaucoma indices. These results were followed by the experience of El-Rafei et al., who after designing a DTI-based, automated segmentation strategy to identify the optic radiation (El-Rafei et al., 2011a,b), enrolled 23 subjects with POAG or NTG, and showed diffuse decrease of FA in the glaucoma group and more localized increase of RD and MD when compared to controls. Interestingly, the Meyer loop showed the highest MD and RD values in glaucoma patients (El-Rafei et al., 2011a,b). In POAG, FA reduction has been demonstrated to involve also other WM tracts such as the inferior fronto-occipital fasciculus, the longitudinal and inferior frontal fasciculi, the caudate nucleus, the putamen, the thalamic radiation, and the anterior and posterior limb of the internal capsule (Zikou et al., 2012). Dai et al. (2013a,b) found that RD of the OR was significantly higher in glaucoma patients than in controls, and that those indexes were positively correlated with clinical stage. Surprisingly, no significant groupwise differences of AD, MD, or FA and no correlation between OR parameters and RNFL were found. However, Chen et al. (2013a,b) used TBSS to show a significant FA decrease and MD increase in the OR. Only FA in the OR was found to correlate with disease stage. The TBSS approach was also employed by Lu et al. in a POAG patient population, showing a significant decrease of FA in the OR of glaucoma patients as compared to controls (Lu et al., 2013). A decrease of FA in the OR which correlated with clinical parameters was also observed by Murai et al. (2013). Recently, Kaushik et al. have used DTI-based tractography to examine OR bundles, also evaluating DTI parameters in two groups of POAG patients which differed in terms of hemifield defect along with a control group. A lower number of bundles were found in both glaucoma groups as compared to controls, and the comparison of DTI parameter showed a FA significant reduction and increase of RD (Kaushik et al., 2014). Evidence from previous studies was collected by the El-Rafei group, which proposed to use a visual pathway analysis based on the DTI segmentation of OR and extraction of features describing the state of its fiber bundles to classify glaucoma patients. This process led to a correct separation of glaucoma patients from normal controls with an accuracy of 92.4%. Also, POAG patients were distinguished from a NTG population with an accuracy of 98.3% (El-Rafei et al., 2013). Also, DTI-related parameters (and FA, in particular) have been shown by Schoemann et al. to correlate with the presence and the entity of white matter lesions in the OR (Schoemann et al., 2014).
4 Functional imaging
4 FUNCTIONAL IMAGING Functional MRI (fMRI) plays a pivotal role in inferring neuronal activity. Compared with positron emission tomography (PET) and single-photon emission computed tomography, this noninvasive imaging technique allows to image response localization following various stimuli with an intrinsically higher spatial resolution and without the need for radioisotope administration. Functional imaging comprises two different MR techniques: blood oxygen level-dependent (BOLD) imaging and arterial spin labeling (ASL) imaging. BOLD imaging is based on the observation of changes in local hemodynamics following neural activity. Changes in blood oxygenation affect the MR signal due to variations in concentration of deoxyhemoglobin, which is a paramagnetic agent. Increased neural activity is followed by upregulation of local blood flow leading to a reduction of relative deoxyhemoglobin concentration at the venular bed, which can be detected using MRI. ASL is based on the effect of the exchange between previously magnetically labeled blood water and the blood water of the ROI. Arterial water is labeled below the ROI with a 180° inversion pulse. The obtained inverted spins which then inflow within the tissue of interest alter the total magnetization determining an MR signal reduction. The use of ASL instead of BOLD has been previously demonstrated to lead to a better activation localization because it focuses prominently on the capillary rather than the venular vascular bed (Duong et al., 2002). The BOLD technique can easily demonstrate visual cortex activation during a stimulation as shown by Logothetis et al. in monkeys (Logothetis et al., 2001). Neural response to a visual stimulus begins within a few hundreds of milliseconds. The reduction of signal intensity, which is the source of BOLD signal, is observed 0.5–2.0 s after the stimulus onset. Visual cortex and striate and extrastriate areas activation was firstly demonstrated by Courtney et al. and Engel et al. exposing the subjects to an expandingcontracting ring stimuli which was known to generate a strong neural response in V1 (Courtney and Ungerleider, 1997; Engel et al., 1997). Following these first experiences, great effort was made to demonstrate the correlation between BOLD– fMRI and traditional visual examination in several pathologic conditions such as hemianopia due to prechiasmatic, chiasmatic and retrochiasmatic lesions, optic neuritis, and space occupying lesions of the optic radiation (Miki et al., 1996). Pathologic activation patterns were also observed in patients affected by dyslexia and in schizophrenics who experienced visual hallucinations (Oertel et al., 2007). BOLD–fMRI can be used to evaluate neural response after a visual stimulus or regional interactions that occur when a subject is not performing an explicit task. The latter is known as resting state fMRI (rsfMRI) and has allowed to demonstrate the existence of several subnetworks of areas which are functionally connected at rest. Based on the experience gained in optic neuropathy, in which the stimulation of the affected eye failed to activate V1 areas corresponding to the central visual field defects (Gareau et al., 1999), Duncan et al. (2007) demonstrated that viewing with the fellow (nonglaucomatous) eye elicited a greater fMRI response in V1 in POAG patients when compared to controls. Additionally, there was a significant agreement
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between the pattern of visual loss and the pattern of BOLD activity in the cortex, and a significant correlation between changes in BOLD response and difference in sensitivity thresholds between the glaucomatous and fellow eye (PDdif ) obtained with standard automated perimetry (Duncan et al., 2007, 2012). Later Qing et al. evaluated POAG patients with spared central vision in a task induced experiment. They found that the cortical response to a checkerboard stimulus presented at the apparently normal central visual field in the glaucomatous eye elicited a less prominent BOLD signal in the visual cortex than if presented at the fellow eye. This was suggested to correlate with daily difficulties in visual tasks which are only partially predicted by the overall visual loss (Qing et al., 2010). Following these task-based BOLD studies, additional attention has been devoted to functional connectivity (FC) and resting state alterations in glaucoma patients. Wang et al. were the first to demonstrate a nonrandom spontaneous activity within the primary visual cortex of normal individuals. They showed a network of brain areas functionally connected with the visual cortex such as visual association areas, the precuneus, the precentral/ postcentral gyrus, the middle frontal gyrus, the fusiform gyrus, the inferior/middle temporal gyrus, and the parahippocampal gyrus (Wang et al., 2008). Dai et al. showed significant differences in activation of functionally connected areas in glaucoma patients as compared to controls. In particular, the activity in the right inferior temporal gyrus (BA37), left middle occipital gyrus (BA19), left postcentral gyrus (BA4), and right superior occipital gyrus (BA19) was decreased in POAG patients. A decrease in positive FC between primary visual cortex and higher cortices suggested a lesser incorporation of visual information with other stimuli leading to diminished integration with language/working memory or sensorimotor information. When comparing these patients to controls, negative FC was demonstrated to disappear between BA17 with the extranuclear regions (BA25), the right temporal, right middle frontal gyrus (BA10), right middle cerebellar peduncle, left cerebellum, and right insular gyrus. This phenomenon could be due to compensation-related recruitment of new areas, as it was previously demonstrated in other neurodegenerative diseases (Dai et al., 2013a,b). Recently, Frezzotti et al. (2014) demonstrated an altered FC in five of eight resting state networks in patients with advanced glaucoma. In particular, a lower FC was found in the working memory network including the superior frontal gyrus (SFG) on the left and the supramarginal gyrus and lateral occipital cortex on the right, in the extrastriate region of the visual network including the right lingual gyrus, and in the dorsal attention network including the lateral occipital cortex bilaterally and pre- and postcentral gyrus on the left. A higher FC was found in the visual network including lateral occipital cortex bilaterally and temporo-occipital fusiform cortex and in the medial part of the executive network including SFG, paracingulate, and anterior cingulate gyrus (Frezzotti et al., 2014). Interestingly, they found an increase of FC with the higher cortices (secondary visual cortex) suggesting a reduction of inhibitory signals from the primary cortex. Altered spontaneous brain activity was also documented by Song et al. who conducted a rsfMRI study in POAG patients. They performed a regional homogeneity (ReHo) analysis based on rsfMRI data. When compared to controls, ReHo values in POAG patients were significantly increased in the right dorsal anterior cingulated cortex, in the bilateral medial fontal
5 Voxel-based morphometry
gyrus and in the right cerebellar anterior lobe and significantly decreased in the bilateral calcarine, bilateral precuneus, bilateral precentral/postcentral gyrus, left inferior parietal lobule, and left cerebellar posterior lobe. A negative correlation between the spontaneous activity of the precuneus and clinical severity was also demonstrated (Song et al., 2014). Liu et al. explored the distribution between abnormal regional intrinsic activities in the glaucomatous brain and their correlation with disease severity. They performed a rsfMRI study on POAG patients measuring the amplitude of low frequency fluctuations (ALFF) in the BOLD signal. Patients showed an ALFF value increase in the right medial frontal gyrus and superior motor area, while a decrease was noted in the right occipital lingual gyrus, right inferior temporal gyrus, and left precentral gyrus when compared to controls. Correlation analysis with the HAP score showed that the ALFF was positively and negatively correlated with the right SFG and the right precentral gyrus on one hand, and the left occipital lobe and left precentral gyrus on the other hand, respectively (Liu and Tian, 2014). Similarly, Li et al. showed decreased ALFF values in the visual cortices, in the posterior default network and in the motor and sensory cortices of glaucoma patients with respect to controls. Increased ALFF values were detected in the prefrontal cortex, left superior temporal gyrus, right middle cingulate cortex, and left inferior parietal lobule. A positive correlation was found between HAP score and ALFF values in the right SFG, while a negative correlation was found with the cuneus. In POAG patients, the HAP score for POAG was positively correlated with ALFF values of the right SFG and negatively correlated with ALFF values of the left cuneus (Li et al., 2015). To our knowledge, there is only one report on the use of ASL fMRI to evaluate cerebral blood flow (CBF) in V1 in glaucoma patients. Ten POAG patients were recruited by Duncan et al., who performed ASL on a 3T MR scanner. CBF resulted significantly lower for regions belonging to the primary visual cortex that corresponded to glaucomatous region of the visual field (Duncan et al., 2012).
5 VOXEL-BASED MORPHOMETRY VBM is a structural processing technique based on the statistical parametric mapping that allows the investigation of focal differences in brain anatomy. It involves a voxel-wise comparison of the local concentration of gray matter (GM) between groups of subjects. The brain images are registered to a template and smoothed so that each voxel represents the average of itself and its neighbors. After modulation of the image by the Jacobian determinant of the resulting warp, local volume is compared across the brain on a voxel basis. There are several studies in which VBM was used to identify volume changes of the visual system GM in glaucoma patients. The majority of these studies showed a decrease GM volume in the occipital and other cortices and in other brain regions such as ON, chiasma, OT, LGN, and OR (Boucard et al., 2009; Hernowo et al., 2011; Zikou et al., 2012). In contrast, Li et al. identified an increase of GM density in the region adjacent to BA39 and, by Chen et al., who demonstrated an increase of GM volume in several locations such as middle temporal gyrus, inferior parietal gyrus, angular gyrus, left superior parietal gyrus, left
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precuneus, and left middle occipital gyrus (Chen et al., 2013a,b; Li et al., 2012). Recently, Bogorodzky et al. described significant cortical thinning around the calcarine sulci (BA17, BA18), in the left middle temporal gyrus and in the fusiform gyrus (BA19) bilaterally and Frezzotti et al., using a VBM style approach, identified regions of GM atrophy in the hippocampus, fronto-orbital cortex, and superior parietal lobule in POAG patients (Bogorodzki et al., 2014; Frezzotti et al., 2014). All these papers on VBM focused only on advanced stage POAG patients or failed to demonstrate GM alterations in the early stages. Recently, William et al. found that 20% of brain structures in POAG patients were larger (in terms of absolute volume) than in controls (right and left inferior occipital gyri and the right middle occipital gyrus, right inferior temporal gyrus, and right occipital lobe white matter), while when analyzing only moderate/advanced stage patients three structures were larger (left inferior occipital gyrus, right middle occipital gyrus, and right superior occipital gyrus) and two smaller (right SFG and corpus callosum) when compared to control (Williams et al., 2013). Similarly, Yu et al. demonstrated a reduction of cortical thickness at the level of V5/MT in mild POAG patients and in anterior V1, V2, and V5/MT in severe glaucomatous patients. Clinical data were shown to significantly correlate with the V5/MT and posterior V2 cortical thickness (Yu et al., 2014). To our knowledge, there are no data in literature focusing on the usefulness of VBM in non-POAG glaucoma patients, however, it appears likely that VBM could be used as an effective tool to demonstrate visual pathway atrophy and compensative regional recruitment in all glaucoma patients.
6 MAGNETIC RESONANCE SPECTROSCOPY Magnetic resonance spectroscopy (MRS) is a noninvasive technique that allows the selective study of metabolite concentration in tissues. The most common strategy is to obtain proton spectra, and the relatively low incidence of motion artifacts (with respect to other body segments) make the brain a suitable organ for MRS imaging. At least three peaks can be identified in the proton MR spectrum: Creatine and Phosphocreatine (Cr), Choline (Cho), and N-acetyl-aspartate (NAA). They represent markers of cellular energy storage, of cytosolic choline compounds such as phosphocholine, glycerophosphocholine, acetylcholine, and others, and of neuronal cellular integrity, respectively. Boucard was the first to analyze proton spectra in age-related macular degeneration and glaucomatous patient along with a control population in a study based on the single voxel MRS of the occipital cortex. His results failed to show any significant difference between patient group and controls in the amount of NAA, Cho, and Cr (Boucard et al., 2007). Additional interest in MRS in glaucoma was generated by the results of a study on a rat model of glaucoma which documented a significant decrease of Cho/Cr ratio in the visual cortex (Chan et al., 2009). In agreement with previous results on humans, Doganay et al. did not find any significant variation in main metabolites but identified a significant increase of glutamine + glutamate (Glx)/Cr ratio, both in the vitreous and in the LGN. This is in accordance with the
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