Morphological Characteristics Of Anterior Visual Pathway And Visual-related Cortex In Primary Open-angle Glaucoma By Using MRI

Backgrounds and objectives:Glaucoma is the second common cause of legal blindness, and its pathogenesis is largely unknown. At present, on the basis of animal models of glaucoma and human autopsies, nerve damage mechanism of glaucoma has been drawn that degenerative change exits in various levels of visual pathway. The researches on morphology and function of glaucoma in vivo has been limited, especially, the systematic researches on structure of visual pathway. The researches on cerebral cortical functions are basically limited to primary visual cortex, but functional changes can not directly represent structural changes. Primary open angle glaucoma (POAG) is known as chronic simple glaucoma with an upgrade incidence rate in recent years, also as an asymptomatic, progressive optic neuropathy characterized by optic nerve lesion and visual field loss. Its initial phases are almost hidden with more complicated pathogenesis than those of primary angle-closure glaucoma. Thus, the study focuses on anterior visual pathway and cerebral visual cortical morphology in terms of POAG. The specific research objectives are as follows:1. Comparative study of the morphological changes characteristics of the visual pathway in POAG patients by establishing the reference values of normal chinese adult optic tracts and optic chiasm.2. To explore the relation between retinal nerve fibre layer defect (RNFLD) and the morphological changed characteristics of Optic Chiasma and optic tracts respectively in POAG patients, and to investigate atrophy and degeneration in anterior visual pathways in POAG.3. To investigate morphological changed characteristics of visual-related cortex in POAG patients with voxel-based morphometry (VBM), to locate and quantify the damage encephalic regions so as to provide the intensive studies of pathomechanism of POAG with a reference of pathological anatomy and provide diagnosis and therapy of POAG with a supported and useful theory.Materials and methods:One thousand healthy Chinese Han adults (aged from 18 to 70 years; 45.82±14.35), collected from December 31th 2006 to December 31th 2008 by means of native multicentral clinical research, were grouped as 18-30 years, 31-40 years, 41-50years, 51-60 years and 61-70 years. Each group had 100 women and 100 men. 37 POAG patients (30 men and 7 women; aged from 23 to 75 years; mean age: 48.86±15.20years), collected from Southwest Hospital and Daping Hospital, were grouped as 9-early-patients, 20-progressed-patients and 8-advanced-patients. All of the patients underwent ophthalmic examinations such as humphrey field analyzer (HFA), optical coherence tomography (OCT), intraocular pressure (IOP) test, etc.The healthy controls (HC) whose visions of naked eyes or corrected eyes were over 0.8 had no visual diseases, while the POAG group have no other eye diseases except for glaucoma. It was confirmed that all the subjects had no histories of familial, genetic and mental diseases and drug addiction after routine physical examinations, laboratory examinations, chest X-rays and neuron system examinations. All of them were informed experimental procedures in detail, and signed informed consents.All the subjects were recruited until being confirmed without cerebral abnormality after scanning including T1WI, T2WI, and fluid attenuated inversion covery (FLAIR) on a SIEMENS Magnetom Sonata 1.5 Tesla whole body MR system. Cerebral 3D volume data were collected with T1WI three-dimensional magnetization prepared rapid acquisition gradient echo sequence (3D-MPRAGE). Structures of optic tracts and optic chiasma were exactly displayed and measured with 3D stereotactic software. Radial lines of various segments of the optic tracts and optic chiasma in HC and POAG groups were measured with double-blind method. Radial lines of optic chiasma definitely contained optic chiasma transverse diameter (OC-TD) in coronal view, optic chiasma height (OC-H), and anteroposterior diameter (APD) in sagittal view; optic tracts contained transverse distance of the cisternal optic tract (TD1), peri-crural optic tract (TD2), height of the cisternal optic tract (H1) and height of peri-crural optic tract (H2). The differences of measurements between POAG and HC were compared by two sample-t-test at a threshold of P<0.05. Also the relation between the measurements of POAG and RNFLT were analysed by pearson linear correlation analysis at a threshold of P<0.05.Brain tissues of 30 POAG patients and 30 gender-, age- and education status- matched HCs were segmented individually by the VBM5.1 toolbox (http://dbm.neuro.uni-jena.de) of SPM5 algorithms (Wellcome Department of Cognitive Neurology, London, UK) under MATLAB 7.1 (The MathWorks, Natick, MA, USA).The result of segment contained gray matters, white matters and cerebrospinal fluids (CSFs). After smoothness for the gray matters at a 8 mm full width at half maximum (FWHM), the HC group and POAG group were performed with two samples t test, whose ages and volumes of the gray matters served as the covariants. The voxels in full brain volume were performed with multiple comparison (P<0.001) (uncorrected). Only if at a threshold of more than 250 voxels were there statistic differences. The brain areas with difference were corrected with small volume correction (SVC) and analyzed in a sphere with 20mm radius centered at the local maxima. It further confirmed that there were statistic differences (P<0.05).Results:1. In the HC group, the reference values of optic tracts were as follows: the left and right TD1 were 4.52±0.56 mm and 4.72±0.60 mm respectively; the left and right TD2 were 3.31±0.41 mm and 3.29±0.40 mm respectively; the left and right H1 were 2.56±0.30 mm and 2.61±0.30 mm respectively; the left and right H2 were 2.44±0.27 mm and 2.42±0.27 mm respectively; and the mean values of OC-TD, APD, and OC-H were 13.54±1.45 mm, 6.66±1.05 mm and 2.53±0.34 mm respectively.In the POAG group, the values of optic tracts were as follows: the left and right TD1 were 4.01±0.82 mm and 3.83±0.78 mm respectively; the left and right TD2 were 3.10±0.59mm and 3.12±0.76 mm respectively; the left and right H1 were 2.13±0.32 mm and 2.23±0.36 mm respectively; the left and right H2 were 1.77±0.38 mm and 1.86±0.33 mm respectively; and the mean values of OC-TD, APD, and OC-H were 12.26±1.60 mm, 6.51±1.46 mm and 2.31±0.36 mm respectively.2. In the POAG group, there were statistic differences in OC-TD and OC-H between the POAG group and the HC group. The measurements were as follows: left and right TD1: t=-5.197, P=0.000; t=-8.623, P=0.000; left and right TD2: t=-2.951, P=0.003; t=-2.445, P=0.015; left and right H1: t=-8.471, =0.000; t=-7.330, P=0.000; left and right H2: t=-14.140, P=0.000; t=-12.085, P=0.000. The APD in sagittal view had no statistic difference (t=-0.854, P=0.393).3. The mean defect (MD) of two-eyed visual-field damage in POAG showed significant correlation with RNFLT positively (left eye: r=0.885, P=0.000; right eye: r=0.758, P=0.000). MD of two-eyes showed significant correlation with the left and right RNFLT positively (r=0.758, P=0.000). The sum of the left and right radial lines of optic tracts showed significant correlation with that of the left and right RNFLT positively (the left and right TD1: r=0.778, P=0.000; the left and right TD2: r=0.777, P=0.000; the left and right H1: r=0.811, P=0.000; the left and right H2: r=0.777, P=0.000). OC-TD and OC-H showed significant correlation with the sum of the left and right RNFLT (OC-TD: r=0.440, P=0.006; OC-H: r=0.6, P=0.000). The positive correlation between optic tracts and RNFLT were greater than that between optic chiasma and RNFLT. APD showed low correlation with RNFLT in sagittal view (r=0.106, P=0.532).4. The results of VBM analysis indicated that early stage POAG patients had no changed gray matter density,on the contrary,aggressive-advanced stage POAG had decreased gray matter density in multiple areas,including both sides of Brodmann 17, 18 and 5, right brodmann 6, 9, 20 and 39, left brodmann 7, 21, 22. The cluster of these regions ranged from 283 to 1633 voxels.There was a cluster (cluster 429 voxels, Talarich coordinate X=34, Y=-63, Z=26) showed increased gray matter density in right middle temporal gyrus Brodmann39. By the side of the most serious damaged brain regions brodmann 39 (cluster 831 voxels, Talarich coordinate X=45,Y=-62,Z=17).5. The results of VBM analysis indicated that early stage POAG patients had no changed in gray matter volume, on the contrary, aggressive-advanced stage POAG had decreased gray matter volume in multiple areas, including both Brodmann 17, 18, 5, right Brodmann 3, 9, 39 and 40, left brodman 7, 20, 22. The cluster of these regions ranged from 313 to 3945 voxels.There was two clusters (cluster1 259 voxels Talarich coordinate X=34, Y=-64, Z=26; cluster2: 276 voxels Talarich coordinate X=55, Y=-2, Z=-20) showed increased gray matter volume by the side of the most serious damaged brain regions brodmann39 (cluster 2245 voxels, Talarich coordinate X=45, Y=-62, Z=17). The location of abnormal brain regions in gray matter density were mostly consistent with that of gray matter volume. Conclusions:1. POAG affects the anterior visual pathway including optic tracts and optic chiasma, and these morphologic changes in the anterior visual pathway are correlated with glaucomatous RNFLD. The degenerative optic tracts and optic chiasma closely correlate with apoptosis degree of retinal ganglion cells (RGCs). There are differences in nerve damage among retina, optic tracts and optic chiasma. MRI examination with high resolution is considered as a valuable tool for evaluating damage of anterior visual pathways in POAG objectively.2. In early stage of POAG, there was still no evidence of morphological damages in visual cortex, which in the further way shows that early stage POAG is the key opportunity to prevent glaucoma from visual loss and damaging to visual-related cortex. During the progressive and advanced stage of POAG, chronic damages on retina give rise to neural degeneration in visual-related cortex, the damaged multi-brain areas have some potential structural-functional correlation, most of them were identified with the structure of dorsal and ventral visual pathways. It can further explore the nervous mechanism of glaucoma and provide sufficient evidence to pathoanatomy, at the same time, it probably exists reconstruction of cortical structure in the neighboring area of severely damaged brain area. The changes in POAG cortex may offer potential clinical value to diagnose and treat glaucoma, may help to develop strategies to protect these glaucomatous damages in future.3. In early stage of POAG, The structures in anterior visual pathway undergo glaucomatous damage,on the contrary, there was still no evidence of morphological damages in visual-related cortex. These results suggest POAG during early stage mainly undergo transneuronal antegrade degeneration, but further observations are needed.