Glaucoma is a neurodegenerative disorder with established relationships with ocular structures such as the retinal nerve fibre layer (RNFL) and the ganglion cell layer (GCL). Ocular imaging techniques such as optical coherence tomography (OCT) allow for quantitative measurement of these structures. OCT has been used in the monitoring of glaucoma, as well as investigating other neurodegenerative conditions such as Alzheimer's disease (AD) and multiple sclerosis (MS). In this review, we highlight the association between these disorders and ocular structures (RNFL and GCL), examining their usefulness as biomarkers of neurodegeneration. The average RNFL thickness loss in patients with AD is 11 μm, and 7 μm in MS patients. Most of the studies investigating these changes are cross-sectional. Further longitudinal studies are required to assess sensitivity and specificity of these potential ocular biomarkers to neurodegenerative disease progression. Eye (2015Eye ( ) 29, 1270Eye ( -1284 doi:10.1038/eye.2015; published online 4 September 2015 IntroductionGlaucoma is a neurodegenerative optic neuropathy manifesting with progressive retinal ganglion cell (RGC) and axonal loss, which can result in visual field defects and blindness because of permanent cellular and neuronal damage. Subjective clinical examination of the optic nerve head (ONH) allows for assessment and monitoring of the structural changes associated with glaucoma. However, objective detection of defects in the peripapillary retinal nerve fibre layer (RNFL) by ophthalmoscopy is difficult. The relationship between glaucoma progression and the structural changes observed at the ONH, RGC layer, and RNFL in glaucoma is well established. [1][2][3][4] Early diagnosis and treatment of glaucoma is vital to maintain visual field, as loss of RGCs is irreversible, 5 and even before any detectable visual field defects, there is a substantial loss of RGCs. Morphological abnormalities can develop 3-5 years before any functional loss is detected. 6 Since the introduction of ocular imaging techniques such as optical coherence tomography (OCT), peripapillary RNFL thickness measurements have been used for the detection and monitoring of glaucoma. 7,8 However, the use of OCT has extended beyond RNFL measurements for glaucoma, and has also been used in the investigation of other neurodegenerative disorders such as Alzheimer's disease (AD) 9-11 and multiple sclerosis (MS). [12][13][14] In addition, given the similarities of brain and retinal foetal angiogenesis, 15,16 retinal microvasculature has also been investigated as a biomarker of changes in cerebral vasculature and cognitive decline. [17][18][19] In this review, we examine the relationships between glaucoma, neurodegenerative disease, and cognitive impairment, and the use of RNFL thickness and RGC loss as potential ocular biomarkers for neurodegenerative disorders such as AD and MS. We review the strength of associations between RNFL and RGC and Eye (2015Eye ( ) 29, 1270Eye ( -1284Eye ( © 2015 Macmillan Publis...

IMPORTANCE Measurement of ganglion cell complex (GCC) thickness may be more sensitive than current methods for glaucoma diagnosis and research. However, little is known about the factors influencing GCC thickness in the general population.OBJECTIVES To investigate the heritability of and factors associated with GCC thickness in a healthy aging population. DESIGN, SETTING, AND PARTICIPANTSA cross-sectional twin study was conducted from August 27, 2014, to March 31, 2016, among 1657 participants of white British ancestry from the TwinsUK study cohort without ocular pathologic conditions. Heritability analyses were conducted in 1432 twins (426 monozygous and 290 dizygous pairs). Association analyses were performed using univariable and multivariable stepwise linear regression models, taking family structure into account. Heritability analyses were conducted using maximum likelihood structural equation twin modeling. MAIN OUTCOMES AND MEASURESParameters measured included GCC thickness, autorefraction, intraocular pressure, blood pressure, body mass index, and cholesterol, creatinine, glucose, insulin, triglycerides, and urea levels. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease formula. RESULTS Among the 1657 participants (mean [SD] age, 56.0 [15.3] years; 89.5% women and 10.5% men), the mean [SD] inner GCC thickness was 96.0 [7.6] μm (95% CI, 95.1-96.2). In multivariable modeling, the mean inner GCC thickness was associated with advancing age (β, -0.14; P < .001), increased body mass index (β, -0.15; P = .001), spherical equivalent (β, 0.70; P < .001), and higher estimated glomerular filtration rate (β, 0.03; P = .02). A 1-U increase in age or body mass index was associated with a 0.14-μm and 0.15-μm decrease in GCC thickness, respectively (P < .001), while a 1-U increase in spherical equivalent or estimated glomerular filtration rate was associated with a 0.70-μm (P < .001) and 0.03-μm (P = .02) increase in GCC thickness, respectively. Ganglion cell complex thickness was not associated with sex, intraocular pressure, or diabetes. Age-adjusted GCC thickness was highly heritable, with additive genetic effects explaining 81% (95% CI, 78%-84%) of phenotypic variance and individual environmental factors explaining the remaining 19% (95% CI, 16%-22%).CONCLUSIONS AND RELEVANCE Ganglion cell complex thickness appears to be highly heritable and further genetic analysis may help identify new biological pathways for glaucoma. The results suggest it may be important to account for age, body mass index, refractive error, and sex when using GCC thickness as a diagnostic tool. Replication of their results is required, as is further research to explain the association between renal function and GCC thickness.

Retinal nerve fibre layer (RNFL) thickness has been associated with cognitive function but it is unclear whether RNFL thinning is secondary to cortical loss, or if the same disease process affects both. We explored whether there is phenotypic sharing between RNFL thickness and cognitive traits, and whether such sharing is due to genetic factors. Detailed eye and cognitive examination were performed on 1602 twins (mean age: 56.4 years; range: 18–89) from the TwinsUK cohort. Associations between RNFL thickness and ophthalmic, cognitive and other predictors were assessed using linear regression or analysis of variance models. Heritability analyses were performed using uni- and bivariate Cholesky decomposition models. RNFL was thinner with increase in myopia and with decrease in disc area (p < 0.001). A thicker RNFL was associated with better performance on mini mental state examination (MMSE, F(5,883) = 5.8, p < 0.001), and with faster reaction time (RT, β = −0.01; p = 0.01); independent of the effects of age, refractive error and disc area (p < 0.05). RNFL thickness was highly heritable (82%) but there was low phenotypic sharing between RNFL thickness and MMSE (5%, 95% CI: 0–10%) or RT (7%, 95% CI: 1–12%). This sharing, however, was mostly due to additive genetic effects (67% and 92% of the shared variance respectively).