Glaucoma Structural Brain Abnormalities in Patients with Primary Open-Angle Glaucoma: A Study with 3T MR Imaging Wei W. Chen,1–3 Ningli Wang,1,3 Suping Cai,3,4 Zhijia Fang,5 Man Yu,2 Qizhu Wu,5 Li Tang,2 Bo Guo,2 Yuliang Feng,2 Jost B. Jonas,6 Xiaoming Chen,2 Xuyang Liu,3,4 and Qiyong Gong5 PURPOSE. We examined changes of the central nervous system CONCLUSIONS. In patients with POAG, three-dimensional MRI in patients with advanced primary open-angle glaucoma revealed widespread abnormalities in the central nervous (POAG). system beyond the visual cortex. (Invest Ophthalmol Vis Sci. 2013;54:545–554) DOI:10.1167/iovs.12-9893 METHODS. The clinical observational study included 15 patients with bilateral advanced POAG and 15 healthy normal control subjects, matched for age and sex with the study group. Retinal rimary open angle glaucoma (POAG) has been defined nerve fiber layer (RNFL) thickness was measured by optical formerly by intraocular morphologic changes, such as coherence tomography (OCT). Using a 3-dimensional magne- P progressive retinal ganglion cell loss and defects in the retinal tization-prepared rapid gradient-echo sequence (3D–MP-RAGE) nerve fiber layer (RNFL), and by corresponding psychophysical of magnetic resonance imaging (MRI) and optimized voxel- abnormalities, such as visual field loss.1 Recent studies by based morphometry (VBM), we measured the cross-sectional various researchers, however, have suggested that the entire area of the optic nerve and optic chiasm, and the gray matter visual pathway may be involved in glaucoma.2–23 Findings from volume of the brain. these experimental studies, human autopsy investigations, and RESULTS. Patients in the POAG group compared to the subjects in vivo neuro-imaging studies of glaucoma patients indicated in the control group showed a significant (P < 0.001) decrease that glaucoma is a complex disorder in which the whole visual in the bilateral gray-matter volume in the lingual gyrus, pathway from the retina to the primary visual cortex may be calcarine gyrus, postcentral gyrus, superior frontal gyrus, involved. These studies, in particular those using neuro- inferior frontal gyrus, and rolandic operculum, as well as in imaging techniques, were limited by the age of the patients the right cuneus, right inferior occipital gyrus, left paracentral with young patients and those with advanced glaucoma usually lobule, and right supramarginal gyrus. Patients in the study not included into the studies, and by focusing on the visual group showed a significant increase in the bilateral gray matter pathway to the visual cortex mostly without examining other volume in the middle temporal gyrus, inferior parietal gyrus, cerebral regions, such as the gray matter in the superior cortex. and angular gyrus, and in the left gray matter volume in the Previous studies indicated, however, that glaucoma damage in superior parietal gyrus, precuneus, and middle occipital gyrus. the receptive fields in the retina could eliminate the In addition, the cross-sectional area of the optic nerve and stimulation of parts of the visual cortex, resulting in the optic chiasm, and RNFL thickness were significantly decreased degeneration of inactive cortical neuronal tissue.14 Therefore, in the POAG group. it has been hypothesized that patients with advanced POAG could experience changes in the whole brain. Also, the neuro- imaging technologies, namely magnetic resonance imaging From the 1Beijing Tongren Eye Center, Medical Sciences College (MRI), have been refined further, resulting in higher spatial of Capital University, Beijing, China; the 2Ophthalmic Laboratories resolution. In addition, optimized voxel-based morphometry and Department of Ophthalmology, West China Hospital, Sichuan (VBM) as a whole-brain, semi-automated technique for University, Chengdu, China; the 4Shenzhen Eye Hospital, Jinan characterizing regional cerebral differences in high-resolution University, Shenzhen, China; the 5West China MR Research Center MRIs with minimal operator dependence has been devel- (HMRRC), Department of Radiology, West China Hospital, Sichuan oped.24 A so-called optimized VBM incorporates additional University, Chengdu, China; and the 6Department of Ophthalmolo- gy, Universit¨atsmedizin Mannheim, Medical Faculty Mannheim, spatial processing steps ahead of the statistical analysis. The Heidelberg University, Mannheim, Germany. optimization steps help in excluding the non-brain voxels 3These authors contributed equally to the work presented here before normalization and subsequent segmentation, and help and therefore should be regarded as equivalent authors. to avoid the potential bias due to systematic differences in skull Supported by the National Natural Science Foundation (Grant size and shape or scalp thickness between the study groups.25 Nos. 81030027, 81227002 and 81220108013), National Key In view of these new neuro-imaging technologies and in view Technologies R&D Program of China (Program No. 2012BAI01B03), of the possibilities of further improvement of the previous and China Postdoctoral Science Foundation (Grant No. investigations, we conducted the present study to examine 2012M520329). The authors alone are responsible for the content and writing of this paper. relatively young patients with advanced glaucomatous optic Submitted for publication March 21, 2012; revised August 26 neuropathy by applying optimized VBM-assisted MRI. and November 16, 2012; accepted December 12, 2012. Disclosure: W.W. Chen,None;N. Wang,None;S. Cai,None;Z. Fang,None;M. Yu,None;Q. Wu,None;L. Tang,None;B. Guo, METHODS None; Y. Feng,None;J.B. Jonas,None;X. Chen,None;X. Liu, None; Q. Gong,None Subjects Corresponding author: Xuyang Liu, Shenzhen Eye Hospital, Jinan University, Shenzhen, 518040, P. R. China; A total of 15 patients (9 men) with an age of 40 to 50 years and bilateral [email protected]. advanced POAG formed the study group, and 15 control subjects Investigative Ophthalmology & Visual Science, January 2013, Vol. 54, No. 1 Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc. 545 Downloaded from iovs.arvojournals.org on 09/28/2021 546 Chen et al. IOVS, January 2013, Vol. 54, No. 1 FIGURE 1. Reconstruction of the axial images perpendicular to the optic nerve. (A) Orbital optic nerve allowing for the construction of a plane parallel to the optic nerve (red line). The middle point was identified along the marked line parallel to the optic nerve from the beginning of the retrobulbar optic nerve to annulus of Zinn. Reconstruction of the targeted plane was performed perpendicular to the optic nerve through the middle point (green line). (B) The sagittal image showing the placement of the reconstruction plane at the middle point of the optic nerve (green line). (C) The reconstructed coronal plane showing the axial targeted image of the optical nerve. matched for age and sex with the study group were included into the MRI Data Acquisition control group of the study. The study followed the tenets of the Declaration of Helsinki, and it was approved by the ethics committee All subjects were examined by a 3 Tesla MRI scanner (Magnetom Trio; of the West China Hospital, Sichuan University Institute, Chengdu, Siemens Co., Erlangen, Germany) with an 8-channel phased-array head Sichuan Province, P.R. China. Informed consent was obtained from the coil as a magnetic resonance signal receiver. The subjects were subjects after explanation. All participants in this study underwent an required to close their eyes and avoid any eye movements during the ophthalmologic examination (visual acuity assessment, refractometry, image acquisition. To secure the repeatability of the MRI scan, the axial measurement of central corneal thickness, slit-lamp–assisted biomi- plane of each MRI session was set parallel to the line from the anterior commissure to the posterior commissure on sagittal localizer images.26 croscopy of the anterior and posterior segment of the eye, applanation The MRI protocol scan contained a transverse-axial turbo spin-echo tonometry, gonioscopy, photography of the optic nerve head and imaging sequence with T2-weighted and a 3-dimensional magnetiza- fundus, and standard automated perimetry; Octopus 101 perimeter; tion-prepared rapid gradient-echo (3D–MP-RAGE) sequence. T2- Interzeag, Bern, Switzerland), and a systematic body examination. All weighed images were used for conventional screening with parame- patients were followed for at least 6 months. The diagnosis of POAG ters: TR/TE ¼ 4000/83 ms and slice thickness 3 mm. Sequence was made by two glaucoma specialists (XL, XC) independently of each parameters for MP-RAGE were: TR/TE ¼ 1900/2.27 ms, field of view other. The inclusion criterion for patients in the study group was (FOV) of 240 3 240 3 170, data matrix of 256 3 256 3 176, resulting in bilateral advanced POAG, as defined by a cup-to-disc diameter ratio an approximate isotropic voxel size 1 3 1 3 1 mm. ‡0.9, a mean perimetric defect ‡15 decibels (dB), preservation of central vision in both eyes, and open anterior chamber angles upon gonioscopy. Exclusion criteria were any other ocular, neurologic or Optic Nerve Cross-Sectional Area Measurement psychiatric disorder; any history or clinical signs of auto-immune Using Syngo MultiModality Workplace (Series Number 3064, Version diseases, cardiovascular diseases, cerebrovascular diseases, and diabe- VE31A; Siemens Co.), we reconstructed axial images perpendicular to tes mellitus; and blood pressure measurements of >140/90 or the optic nerve through the middle point along the line between the antihypertensive medication. retrobulbar optic nerve and annulus tendineus of Zinn (Fig. 1A). The All study participants underwent measurement of the RNFL region of interest (ROI) of the optic nerve was drawn manually in the thickness by optical coherence tomography (OCT, Heidelberg Spec- reconstructed plane (Figs. 1, 2). To ensure the reliability of the ROI tralis OCT; Heidelberg Engineering Co. Heidelberg, Germany). The fast measurement, the same procedure was performed 3 times by three measurement scan protocol was used (3.4 mm diameter). The scanning radiologists (ZF, QW, XH) in a masked manner.