Structural Abnormalities of the Optic Nerve and Retina in Huntington’s Disease Pre-Clinical and Clinical Settings

Abstract

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related pathological remodelling has been reported in HD mouse models and HD carriers. In this study, we studied structural abnormalities in the optic nerve by employing Spectral Domain Optical Coherence Tomography (SD-OCT) in pre-symptomatic HD carriers of Caucasian origin. Transmission Electron Microscopy (TEM) was used to investigate ultrastructural changes in the optic nerve of the well-established R6/2 mouse model at the symptomatic stage of the disease. We found that pre-symptomatic HD carriers displayed a significant reduction in the retinal nerve fibre layer (RNFL) thickness, including specific quadrants: superior, inferior and temporal, but not nasal. There were no other significant irregularities in the GCC layer, at the macula level and in the optic disc morphology. The ultrastructural analysis of the optic nerve in R6/2 mice revealed a significant thinning of the myelin sheaths, with a lamellar separation of the myelin, and a presence of myelonoid bodies. We also found a significant reduction in the thickness of myelin sheaths in peripheral nerves within the choroids area. Those ultrastructural abnormalities were also observed in HD photoreceptor cells that contained severely damaged membrane disks, with evident vacuolisation and swelling. Moreover, the outer segment of retinal layers showed a progressive disintegration. Our study explored structural changes of the optic nerve in pre- and clinical settings and opens new avenues for the potential development of biomarkers that would be of great interest in HD gene therapies.

Characterizing differences in retinal and choroidal microvasculature and structure in individuals with Huntington’s Disease compared to healthy controls: A cross-sectional prospective study

“…The attenuated GCIPL thickness found in our study confirms prior work that identified thinning in both the ganglion cell layer and the inner plexiform layer in individuals with [41,42]. In contrast, our study focused on individuals who were genetically positive and in the prodromal or motor manifest disease stage, and therefore had a more advanced form of HD than the 2 prior which could account for the differences seen in GCIPL thickness.…”

“…HD[40]. Interestingly, GCIPL attenuation was not found by Mazur-Michałek et al and Schmid et al[41,42]. Both papers had slightly different cohorts than our study, with Mazur-Michałek et al studying asymptomatic individuals who were genetically positive for HD and Schmid et al studying both individuals who were genetically positive and in the asymptomatic or the prodromal disease stage…”

“…The attenuated GCIPL thickness found in our study confirms prior work that identified thinning in both the ganglion cell layer and the inner plexiform layer in individuals with symptomatic HD [ 40 ]. Interestingly, GCIPL attenuation was not found by Mazur- Michałek et al and Schmid et al [ 41 , 42 ]. Both papers had slightly different cohorts than our study, with Mazur-Michałek et al studying asymptomatic individuals who were genetically positive for HD and Schmid et al studying both individuals who were genetically positive and in the asymptomatic or the prodromal disease stage [ 41 , 42 ].…”

“…Interestingly, GCIPL attenuation was not found by Mazur- Michałek et al and Schmid et al [ 41 , 42 ]. Both papers had slightly different cohorts than our study, with Mazur-Michałek et al studying asymptomatic individuals who were genetically positive for HD and Schmid et al studying both individuals who were genetically positive and in the asymptomatic or the prodromal disease stage [ 41 , 42 ]. In contrast, our study focused on individuals who were genetically positive and in the prodromal or motor manifest disease stage, and therefore had a more advanced form of HD than the 2 prior which could account for the differences seen in GCIPL thickness.…”

Reflexive and voluntary saccadic eye movements as biomarker of Huntington’s Disease

“…Saccade deficits have been well documented in premanifest and manifest HD patients, and are considered potential biomarkers of disease development and progression [5][6][7][8][9][10][11][12][13][14][15][16][17]. The structural abnormalities of the optic nerve and retina displayed in pre-symptomatic HD carriers could be other potential biomarkers that would be of great interest in HD gene therapies [18]. Recently, impaired smooth pursuit of eye movement was described in an atypical motor presentation of HD with dominant dystonic symptoms at the onset of the disease [19].…”