Diffusion Tensor Imaging Detects Rarefaction of Optic Radiation in Glaucoma Patients

Diffusion Tensor Imaging Detects Rarefaction of Optic Radiation in Glaucoma Patients

Diffusion Tensor Imaging Detects Rarefaction of Optic Radiation in Glaucoma Patients Tobias Engelhorn, MD, Georg Michelson, MD, Simone Waerntges, MD, ...

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Diffusion Tensor Imaging Detects Rarefaction of Optic Radiation in Glaucoma Patients Tobias Engelhorn, MD, Georg Michelson, MD, Simone Waerntges, MD, Tobias Struffert, MD, Sultan Haider, MSc, Arnd Doerfler, MD Rationale and Objectives: Diffusion tensor imaging (DTI) can depict rarefaction of the optical fibres. Hence, we applied DTI to assess pathological changes of the optic radiation in glaucoma patients. Materials and Methods: Fifty glaucoma patients and 50 healthy age-matched controls were examined by a 3T high-field magnetic resonance scanner. Fiber tracts were volume rendered using a semiquantitative approach to assess rarefaction and results were correlated with the extent of optic nerve atrophy and reduced spatial-temporal contrast sensitivity of the retina using established ophthalmological examinations. Results: Twenty-two glaucoma patients (44%) showed significant rarefaction of the optic radiation: the volume was reduced to 67  16% compared with controls. Hereby, the glaucomatous optic nerve atrophy stage correlated with the presence of DTI-derived rarefied optic radiation (Kendall tau-b 0.272, P = .016). Aside, cerebral microangiopathy affecting the optic radiation was significantly higher among glaucoma patients compared to controls (10 patients compared with 2 patients, P < .05). Conclusion: In patients with glaucomatous optic nerve atrophy, there is anterograde and—most likely because of microangiopathic lesions within the optic radiation—retrograde transneuronal rarefaction of the optic radiation that can be assessed in vivo using DTI with good correlation to established ophthalmological examinations. Key Words: Glaucoma; DTI, cerebral microangiopathy; transneuronal degeneration. ªAUR, 2011

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ransneuronal degeneration is a process of primary neuron injury affecting the linked distal neurons. It was described for pathophysiological changes in neurological diseases such as Alzheimer disease (1) and brain trauma (2). More recent studies have suggested that this damage also occurs in the development of glaucoma (3–5). Loss of ganglion cells in the retina (first and second neuron of the visual pathway) and their axons representing the optic nerve (third neuron) (6) and a loss of astrocytes (7) is, because of an increased intraocular pressure, the predominant finding in glaucoma. The axons of various retinal ganglion cell subtypes, differing in specific morphology and function, exit the eye ball, and finally converge to anatomically distinguishable layers of the lateral geniculate nucleus (LGN) (8) where a loss of neural cells has also been described for

Acad Radiol 2011; 18:764–769 From the Departments of Neuroradiology (T.E., T.S., A.D.) and Ophthalmology (G.M., S.W.), University Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany; Siemens AG Healthcare Sector, Erlangen, Germany (S.H.). Received November 17, 2010; accepted January 22, 2011. T. Engelhorn and G. Michelson contributed equally to this work and thus, share first authorship. Address correspondence to: T.E. e-mail: tobias. [email protected] ªAUR, 2011 doi:10.1016/j.acra.2011.01.014

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glaucoma (9). The LGN serves as a relay station transmitting the information via the optic radiation (fourth neuron of the visual pathway) to the primary visual cortex (9). The loss of axons and astrocytes, which are placed between the optic nerve fibers can be revealed in ophthalmological examinations by a ‘‘cupping’’ of the optic nerve head (10). Glaucoma results in a loss of visual function, which is detectable by determination of the visual field and reduced spatial-temporal contrast sensitivity of the retina using the frequency doubling test (FDT) (11). It is not clear if the loss of axons of the optic nerve causes directly a transneuronal antegrade injury of the optic radiation in humans. However, animal experiments recently have shown that glaucomatous loss of axons of the optic nerve is followed by a loss of the LGN volume indicating a reduced number of neurons (9). Ischemic injury of the optic radiation may be assumed as further mechanism to damage the retinal ganglion cell axons upstream: a transneuronal retrograde degeneration of retinal ganglion cells was described following striate cortical injury precluding interruption of the vascular supply to the thalamus and optic tract in cats (12). In vivo detection of glaucomatous changes along the visual pathway and its conjunction to intraocular findings poses a special challenge. Since its introduction a decade ago, diffusion tensor imaging (DTI)) and its application, DTI fiber

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tractography, has become a prominent tool for mapping white matter axonal structures and investigating their structural integrity in the human brain and in animal settings. Applying DTI reconstructions to the human visual system, visualization of the optic radiation is possible noninvasively within minutes as demonstrated recently (13). Hence, we applied DTI to assess pathological changes of the optic radiation in glaucoma patients compared to age-matched controls with normal eyes. METHODS Patient Population

This observational case control study was conducted in accordance with the Declaration of Helsinki on Biomedical Research Involving Human Subjects. The Clinical Investigation Ethics Committee of the University of ErlangenNuremberg approved the study protocol, and written informed consent was obtained from all subjects (glaucoma patients and controls) before the study after explanation of the nature and possible consequences of the study (Figs 1 and 2). Fifty patients (18 men, 32 women; mean age 52.2  12.6 and 60.0  16.9 years, respectively) diagnosed with a damage of the optic nerve head or visual disturbance without signs of glaucomatous or non-glaucomatous optic nerve atrophy, were randomly selected for magnetic resonance imaging (MRI) and subsequent DTI. Fifty age-matched patients without glaucoma undergoing MRI because of headaches, dizziness, or stenosis of the nasolacrimal duct served as controls (22 men, 28 women; mean age 54.0  14.2 and 61.4  15.1 years, respectively). In these patients, increased intraocular pressure (IOP), optic nerve head atrophy or visual disturbances were excluded by an ophthalmological examination. Glaucoma patients and controls received a questionnaire requesting age, gender, height, weight, known cardiovascular risk factors (ie, arterial hypertension, diabetes, hypercholesterolemia, smoking history), cardiovascular events (myocardial infarction, peripheral arterial disease, and stroke), and current medication. In glaucoma patients, eyes were assessed by an extended ophthalmological examination. Available additional examinations were referred to for evaluation, that is HRT (Heidelberg Retina Tomograph, Heidelberg, Germany), automated perimetry (Octo 101 dG2, Interzeag, Schlieren, Switzerland), spatial-temporal contrast sensitivity (FDT, Carl Zeiss Meditec AG, Jena, Germany), non-mydriatic fundus images (KOWA, nonmyd-alpha 45, Japan), and measurement of IOP. Grading of Optic Nerve Head Damage

Diagnosis of glaucomatous optic nerve atrophy was based on evaluation of fundus photographs showing loss of the rim area and increased parapapillary chorioretinal alpha and beta zones (14,15). In case of doubt, findings of visual field loss and HRT were factored in grading. Stage 0 indicates a normal optic nerve head and stage 4 a substantially advanced damage of the optic nerve head. For evaluation the mean value of the stage of both eyes was chosen.

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Determination of the Frequency Doubling Test Score

The FDT Version C-20-5 (16) measures the spatial-temporal contrast sensitivity of the retina. The visual field is divided in 4  4 square fields with a 17th field in the middle, which represents the site of the sharpest vision. A mild relative loss of the spatial-temporal contrast sensitivity is defined as the probability that the defect is normal in <5% compared with age-adjusted healthy subjects (A). A moderate relative loss is normal in <2% (B), and a severe loss is normal in <1% of the healthy people (C). The FDT score is the sum of the fields multiplied by A  1, B  2, and C  3. Considering the fact that in humans nearly 50% of the retinal ganglion cells of the nasal retina are crossing to the contralateral side the FDT scores for the homonymous visual fields corresponding to the respective optic radiation were calculated. MRI

MRI was performed on a 3T high-field scanner (Magnetom Tim Trio, Siemens, Erlangen, Germany) with a gradient field strength up to 45 mT/m (72 mT/m effective). The anatomical data were obtained in a T1-weighted three-dimensional magnetization-prepared rapid gradient-echo sequence (repetition time = 900 ms, echo time = 3 ms, FOV = 23  23 cm, acquisition matrix size = 512  256 reconstructed to 512  512, reconstructed axial plans with 1.2-mm slice thickness). For detection of microangiopathy, a heavily T2-weighted fluid-attenuated inversion recovery sequence covering the whole brain was acquired (repetition time = 10,000 ms, echo time = 115 ms, matrix size = 512  512). DTI was performed in the axial plane with 4-mm slice thickness and no interslice separation using a single-shot, spin echo, echo planar imaging diffusion tensor sequence thus covering the whole visual pathway (repetition time = 3400 ms, echo time = 93 ms, field of view = 23  23 cm, acquisition matrix size = 256  256 reconstructed to 512  512, number of signal averages = 7, partial Fourier acquisition = 60%). Diffusion weighting with a maximal b-factor of 1000 s/mm2 was carried out along 15 icosahedral directions complemented by one scan with b = 0. Datasets were automatically corrected for imaging distortions and co-registered in reference to T1-weighted magnetization-prepared rapid gradient-echo images. These and further calculations such as determining the independent elements of the diffusion tensor, deriving the corresponding eigenvalues and eigenvectors, and reconstructing and volume rendering fibers, were performed with a dedicated software package (Neuro 3D, Siemens Healthcare AG, Erlangen, Germany). Reconstruction and volumetry of the optic radiation was done as recently described in detail (13). Assessment of Microangiopathy

Microangiopathic lesions were graded by two experienced neuroradiologists as (I) mild, (II) moderate, and (III) severe (17). 765

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Figure 1. Woman, 68 years of age OD/OS with primary open angle glaucoma, in OS a parapapillary bleeding of the optic nerve head. (a) In both eyes (OS [left] > OD [right]) the automated perimeter showed predominantly superior visual field defects due to a loss of axons of the 3rd neuron. (b) The frequency doubling test indicated impaired spatial-temporal contrast sensitivity primarily in OS in the superior and temporal area as well as nasal near the center. (c) Typical signs of glaucomatous optic nerve atrophy were recorded by a non-mydriatic fundus camera that is in OS a small rim area, smaller inferior rim than temporal and a parapapillary bleeding (arrows). (d) DTI shows intact optic radiation in a healthy 67year-old woman without any visual disturbances. (e) DTI reveals significant rarefication of the optic radiation compared to the age-matched control (arrows). DTI, diffusion tensor imaging; OD, right eye; OS, left eye.

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Figure 2. Generalized microangiopathy was coexistent with optic nerve head damage in 30 of 49 patients. Here, 10 patients showed remarkable microangiopathic lesions within the optic radiation (8 patients with glaucomatous optic nerve atrophy and 2 patients with nonglaucomatous optic nerve atrophy, respectively) and DTI revealed rarefication of the optic radiation in 8 of these 10 patients. An example is given in (a) and (b) (T2-weighted fluid-attenuated inversion recovery [FLAIR] sequence). DTI, diffusion tensor imaging.

Data Analysis

Analyses were performed using the SPSS software (release 16.0, SPSS Inc, Chicago, IL). Kendall-tau-b was applicable for stages of diseases. Spearman-rho was used for partial correlation analysis. The Goodman and Kruskal lambda analyzed the relation of the rarefied optic radiation with the siderelated visual field defects. The coefficient eta2 stated to which extent the mean values of the dependent variable differ between the different categories of the independent variable. A level of P # .05 was considered to be significant. RESULTS In all control subjects ophthalmological and neuroradiological examinations did not provide an indication of glaucomatous optic nerve atrophy, visual disturbance, or irregularly developed optic radiation. One of 50 patients with glaucomatous optic nerve atrophy was excluded because of severe signs of multiple sclerosis; consequently, 49 glaucoma patients were included in this study. Concomitant diseases of the study population (glaucoma patients and controls) are shown in Table 1. Ophthalmic Examination

In all glaucoma patients except one the visual field was examined by automated perimetry and/or FDT; results are shown in Table 2. The visual field examined by automated perimetry or FDT was significantly affected in 47% and in 68% of glaucoma patients, respectively. The morphological sign of a reduced retinal nerve fiber layer thickness was found in 62% in patients. The grading of optic nerve atrophy in the right/left eye of glaucoma patients is shown in Table 3. MRI

The occurrence of microangiopathy among glaucoma patients and controls is shown in Table 4. Generalized microangiopathy was found in 30 of 49 glaucoma patients (61%; 14 patients with grade I, 11 patients with grade II, and 5 patients with

TABLE 1. Concomitant Diseases of the Glaucoma and Control Population Concomitant Disease Arterial hypertension Arterial hypotension Hypercholesterolemia Diabetes Brain infarction Myocardial infarction Peripheral arterial disease Affections of the thyroid gland Cancerogenic diseases including brain Hyperuricemia Failure of heart or cardiac valves Surgery of carotid artery Multiple sclerosis

Glaucoma Patients Controls 23 1 14 4 3 1 1 9 7

19 0 11 2 2 1 2 6 6

3 3 1 1

2 5 2 0

grade III, respectively) and in 20 of 50 controls (40%; 9 patients with grade I and 11 patients with grade II, respectively). Circumscribed microangiopathy within the optic radiation was found in 10 glaucoma patients and in two controls. As result of DTI, 22 of 49 glaucoma patients (44%) had at least a slight rarefaction of the optic radiation (averaged rendered volume <85% compared with controls). In these patients, the averaged rendered volume of the optic radiation (both sides) was reduced to 67  16% compared with controls. In 6 of these 22 patients (27%), both sides showed similar reduction (difference less than 10%), whereas in 14 patients (63%) one side was more rarefied: in 9 patients the left side, in 5 patients the right side). None of the 49 patients showed exclusive reduction of the optic radiation of only one side with a normal contralateral side. Aside, 8 of 10 (80%) glaucoma patients with circumscribed microangiopathy within the optic radiation revealed rarefaction of the optic radiation. Correlation between Ophthalmic Examination and MRI

Correlations were found for the presence/absence of rarefied optic radiation, the stage of microangiopathy, and the stage of 767

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TABLE 2. Characterization of the Glaucoma Patients by Ophthalmologic Findings Ophthalmologic Findings in Glaucoma Patients Age (y) FDT duration (#50 s) OD OS FDT score (#5) OD OS Mean defect (#4) OD OS Corrected refraction OD OS IOP (<22 mm Hg) OD OS HRT disk area (1.69‒2.82 mm2) OD OS HRT cup area (0.26‒1.27 mm2) OD OS HRT rim area (1.20‒1.78 mm2) OD OS RNFL thickness (0.18‒0.31 mm) OD OS

Mean 57.3

TABLE 3. Grading of Optic Nerve Atrophy in the Right/Left Eye of Glaucoma Patients

SD 15.9

0 13/13

66.7 72.0

34.8 33.0

13.5 14.1

16.4 13.9

4.8 4.3

6.1 5.3

0.76 0.73

0.30 0.26

14.9 15.3

4.2 4.3

2.326 2.353

0.596 0.643

1.051 1.108

0.512 0.611

1.276 1.246

0.511 0.613

0.194 0.194

0.062 0.124

OD, right eye; OS, left eye; FDT, frequency doubling test (loss of spatial-temporal contrast sensitivity: A = mild relative >95%, B = moderate relative >98%, C = severe >99%; number of fields of a maximum of 17); FDT score, sum of fields multiplied by A*1, B*2, and C*3. Mean defect, visual field defect determined by Octopus perimeter; IOP, intraocular pressure; HRT, Heidelberg retinal tomograph; RNFL, retinal nerve fiber layer. Normal values are given in brackets.

optic nerve atrophy. One-tailed analysis of data revealed a correlation of the stage of optic nerve atrophy with the presence of rarefied optic radiation (Kendall tau-b [Ktb] 0.272, P = .016) and with the stage of cerebral microangiopathy (Ktb 0.252, P = .016). The homonymous visual field defect scores were related to the corresponding rarefaction of the optic radiation (right: lambda = 0.600, asymptotic SE = 0.126, P = .00034; left: lambda = 0.733, asymptotic SE = 0.124, P = .00024). 768

Grading of Optic Nerve Atrophy in Glaucoma Patients Right Eye/Left Eye 1

2

3

4

Total

8/11

9/10

7/5

12/10

49/49

Grading 0 = normal optic nerve head, 4 = substantially advanced damage of the optic nerve head.

TABLE 4. Microangiopathy in Glaucoma Patients and Controls Glaucoma Patients MA No MA MA inside the optic radiation MA outside the OR Rarefaction of the OR with MA inside the OR Rarefaction of the OR with MA outside the OR Rarefaction of the OR without MA

Controls Statistics

30 20 10 20 8

20 30 2 18 0

P < .05 P < .05 P < .05 P = .87 P < .05

9

0

P < .05

5

0

P < .05

MA, microangiopathy; OR, optic radiation.

DISCUSSION The pathophysiology of glaucoma is based on a damage of the neurons of the retina (first and second neuron of the visual pathway) and the optic nerve (third neuron of the visual pathway) with progressive loss of function. It is discussed that transneuronal degeneration to the optic radiation (fourth neuron of the visual pathway, connected to the third neuron in the LGN) proceeds. Most studies examined primate models of experimentally induced glaucoma. It was reported that in unilateral experimental glaucoma in addition to the damage of retinal ganglion cells also the postretinal magno- and parvocellular layers of the LGN of the thalamus (3) and the primary visual cortex may be impaired (9). Transneuronal degeneration was also found in a postmortem human study of the optic nerve, LGN, and visual cortex (7). Additionally, neuronal degeneration was shown to proceed from the LGN to the visual cortex in a primate model of glaucoma (18,19). Hereby, transneuronal degeneration seems to be progressive with increasing nerve fiber loss in the optic nerve (9). According to Harwerth and Quigley, a loss of approximately 50–60% of the ganglion cells may be already present if visual field defects are detectable by perimetry (20). Besides, it was shown in experimental glaucoma that some neurons in the LGN have died and surviving neurons were atrophic (3–5). Because impairment of the visual field is associated with optic nerve degeneration a certain probability for neurodegeneration of the optic radiation may be adopted.

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The goal of this study was to proof the concept of transneuronal degeneration in glaucoma patients involving the optic radiation in case of optic nerve atrophy using DTI. This clinically well-established MRI technique is based on the random motion of water molecules, which is associated with their thermal energy at body temperature (Brownian motion) (21). In white matter consisting of axons in all directions of a three-dimensional space the diffusion of free water molecules is different (anisotropy) (22,23). Predominantly the orientation of fiber tracts and their micro- and macrostructural features influences the diffusion anisotropy (24) and provide the direction of the largest eigenvector. Macroscopically the degree of anisotropy assigned to a definite voxel is affected by the variability in the orientation of all white matter tracts in this imaging voxel (24). Using DTI, we could recently demonstrate that reconstruction of the optic radiation can be done noninvasively using a robust and fast semiquantitative approach (13). To our best knowledge, this is the first study using in vivo DTI fiber tractography to examine the optic radiation in 50 patients with glaucomatous optic nerve atrophy and typical visual field defects compared to controls (in controls, increased IOP, optic nerve atrophy, and visual field defects were excluded by an ophthalmological examination). As age influences significantly both glaucomatous optic nerve atrophy (25,26) and the volume of the optic radiation (13), rendered volumes were compared with age-matched controls. Hereby we could demonstrate, that significant rarefaction of the respective optic radiation was found in nearly half of the examined patients (44%). Importantly, the extent of rarefaction of the optic radiation correlated with the extent of optic nerve atrophy and the extent of visual field defects. Hence, we conclude that there is anterograde transneuronal degeneration of the optic radiation in glaucoma patients dependent to the severity of damage to the retinal neurons and the neurons in the optic nerve. Interestingly, the occurrence of microangiopathic lesions within the optic radiation was significantly higher among glaucoma patients compared with controls, whereas the occurrence of microangiopathy outside the optic radiation was in both groups in the same range. Aside, 80% of glaucoma patients with microangiopathic lesions within the optic radiation revealed significant rarefaction of the optic radiation supporting the concept of retrograde degeneration of retinal ganglion cells starting from the optic radiation caused by microangiopathic lesions. Hence, microangiopathic lesions within the optic radiation are not only a cofactor but a cause for retrograde glaucomatous optic nerve atrophy. At least for degenerative changes in the LGN a contribution to progressive retinal ganglion cell injury and loss was considered possible by interfering with both anterograde and retrograde axonal transport systems between the eye and the LGN in glaucomatous optic nerve atrophy (7). In conclusion, there is rarefaction of the optic radiation in glaucoma patients. The extent of rarefaction can be assessed in vivo noninvasively using DTI with good correlation to established ophthalmological examinations. Thereby, this

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technique could play an important role in the detection and follow-up of glaucoma patients. REFERENCES 1. Su JH, Deng G, Cotman CW. Transneuronal degeneration in the spread of Alzheimer’s disease pathology: immunohistochemical evidence for the transmission of tau hyperphosphorylation. Neurobiol Dis 1997; 4:365–375. 2. Conti AC, Raghupathi R, Trojanowski JQ, et al. Experimental brain injury induces regionally distinct apoptosis during the acute and delayed posttraumatic period. J Neurosci 1998; 18:5663–5672. 3. Yuecel YH, Zhang Q, Weinreb RN, et al. Atrophy of relay neurons in magno- and parvocellular layers in the lateral geniculate nucleus in experimental glaucoma. Invest Ophthalmol Vis Sci 2001; 42:3216–3222. 4. Yuecel YH, Zhang Q, Gupta N, et al. Loss of neurons in magnocellular and parvocellular layers of the lateral geniculate nucleus in glaucoma. Arch Ophthalmol 2000; 118:378–384. 5. Weber AJ, Chen H, Hubbard WC. Experimental glaucoma and cell size, density, and number in the primate lateral geniculate nucleus. Invest Ophthalmol Vis Sci 2000; 41:1370–1379. 6. Fechtner RD, Weinreb RN. Mechanisms of optic nerve damage in primary open angle glaucoma. Surv Ophthalmol 1994; 39:23–42. €l de Tilly L, et al. Human glaucoma and neural degen7. Gupta N, Ang LC, Noe eration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex. Br J Ophthalmol 2006; 90:674–678. 8. Dacey DM. Circuitry for color coding in the primate retina. Proc Natl Acad Sci U S A 1996; 93:582–588. 9. Yuecel YH, Zhang Q, Weinreb RN, et al. Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. Prog Retin Eye Res 2003; 22:465–481. 10. Flammer J, Mozaffarieh M. What is the present pathogenetic concept of glaucomatous optic neuropathy? Surv Ophthalmol 2007; 52:162–173. 11. Anderson A, Johnson CA. Frequency-doubling technology perimetry. Ophthalmol Clin North Am 2003; 16:213–225. 12. Johnson H, Cowey A. Transneuronal retrograde degeneration of retinal ganglion cells following restricted lesions of striate cortex in the monkey. Exp Brain Res 2000; 132:269–275. 13. Engelhorn T, Haider S, Michelson G, et al. A new semi-quantitative approach for analyzing 3T diffusion tensor imaging of optic fibres and its clinical evaluation in glaucoma. Acad Radiol 2010; 17:1313–1316. 14. Jonas JB, Gusek GC, Naumann GO. Optic disc morphometry in chronic primary open-angle glaucoma. I. Morphometric intrapapillary characteristics. Graefes Arch Clin Exp Ophthalmol 1988; 226:522–530. ndez MC, Naumann GO. Parapapillary atrophy and retinal 15. Jonas JB, Ferna vessel diameter in nonglaucomatous optic nerve damage. Invest Ophthalmol Vis Sci 1991; 32:2942–2947. 16. Anderson AJ, Johnson CA. Frequency-doubling technology perimetry. Ophthalmol Clin North Am 2003; 16:213–215. 17. Fazekas F, Schmidt R, Kleinert R. The spectrum of age-associated brain abnormalities: their measurements and histopathological correlates. J Neural Transm Suppl 1998; 53:31–39. 18. Crawford ML, Harwerth RS, Smith EL, et al. Experimental glaucoma in primates: changes in cytochrome oxidase blobs in V1 cortex. Invest Ophthalmol Vis Sci 2001; 42:358–364. 19. Lam DY, Kaufman PL, Gabelt BT, et al. Neurochemical correlates of cortical plasticity after unilateral elevated intraocular pressure in a primate model of glaucoma. Invest Ophthalmol Vis Sci 2003; 44:2573–2581. 20. Harwerth RS, Quigley HA. Visual field defects and retinal ganglion cell losses in patients with glaucoma. Arch Ophthalmol 2006; 124:853–859. 21. Melhem ER, Mori S, Mukundan G, et al. Diffusion tensor MR imaging of the brain and white matter tractography. Am J Roentgenol 2002; 178:3–16. 22. Chenevert TL, Brunberg JA, Pipe JG. Anisotropic diffusion in human white matter: demonstration with MR techniques in vivo. Radiology 1990; 177: 401–405. 23. Moseley ME, Cohen Y, Kucharczyk J, et al. Diffusion-weighted MR imaging of anisotropic water diffusion in cat central nervous system. Radiology 1990; 176:439–445. 24. Pierpaoli C, Jezzard P, Basser PJ, et al. Diffusion tensor MR imaging of the human brain. Radiology 1996; 201:637–648. 25. Koennecke HC. Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications. Neurology 2006; 66:165–171. 26. Elolia R, Stokes J. Monograph series on aging-related diseases: XI. Glaucoma. Chronic Dis Can 1998; 19:157–169.

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