Detection of retinal nerve fiber layer degeneration in patients with Alzheimer's disease using optical coherence tomography: searching new biomarkers

Abstract

At the present time, researchers are searching for biomarkers and tools to detect the Alzheimer's disease (AD) in early phases, especially in high-risk families, and to monitor disease progression. Recent studies have revealed degenerative changes in optic nerve fibers, causing thinning of the retinal nerve fiber layer (RNFL) in patients with AD (Berisha et al. 2007; Kirbas et al. 2013). The RNFL comprises axons originating in retinal ganglion cells and can be measured using ocular imaging technologies such as optical coherence tomography (OCT), which provides non-invasive, rapid, objective and reproducible measurements. Retrograde loss of nerve fibers in the retina and optic nerve may be an early biomarker of neurodegeneration in AD, even prior to hippocampal damage, which impacts memory (Valenti 2007). Following this trend, we conducted a study in which we compared RNFL thickness in healthy and AD subjects using the two most commonly available spectral-domain (SD)-OCT machines [Cirrus OCT (Carl Zeiss Meditec, Inc., Dublin, Ireland) and Spectralis OCT (Heidelberg Engineering, Inc., Carlsbad, CA, USA)]. To carry out this prospective, cross-sectional study, 57 patients with mild or moderate AD and 57 healthy, age-matched control subjects were included. Inclusion criteria were: confirmed AD diagnosis; best-corrected visual acuity (BCVA) of 0.1 or higher; and intra-ocular pressure <21 mmHg. Exclusion criteria were: presence of significant refractive errors (>5 dioptres of spherical equivalent refraction or three dioptres of astigmatism); systemic conditions that could affect the visual system and history of ocular trauma or concomitant ocular diseases. Each eye was considered separately; one eye from each subject was randomly selected to be included in the analyses, except when one of the eyes was excluded (due to the presence of significant media opacity). All subjects underwent visual acuity, colour vision and OCT examinations using two SD-OCT devices. One hundred and fourteen eyes were evaluated: 57 eyes from patients with AD and 57 eyes from healthy subjects. To establish this cohort, we examined 65 patients with AD, but eight patients were not included in the study for the presence of unknown eye disease (two cases) or their inability to perform the full exploration protocol due to their functional status (six cases). Mean age was 75.29 ± 8.64 years in the AD group and 74.77 ± 9.24 years in the control group. Mean disease duration was 3.71 years (range, 1.46–5.96 years). Age, sex and intra-ocular pressure did not differ significantly between healthy controls and patients with AD (p > 0.05). RNFL thickness measured with the two OCT devices is shown in Table 1. Cirrus OCT revealed significant RNFL thinning in patients with AD especially in the superior and the inferior quadrant. The Spectralis OCT classic glaucoma application and the Nsite Axonal Analytics application revealed significant thinning in the inferior and inferotemporal RNFL in patients with AD compared with controls. There is histopathologic evidence of retinal ganglion cell loss and optic nerve degeneration in patients with AD (Blanks et al. 1996). Thus, we postulate that axonal loss secondary to other pathologic changes that occur in the brain can be detected by scanning the RNFL and the optic nerve, as these non-myelinated axons form the optical path that culminates in the occipital cortex. Although we believe the OCT could potentially provide a biomarker of AD, it should take into account a series of limitations: the relatively small sample size (despite being larger than that in previous studies) and the exclusion of subjects with mild cognitive impairment (preclinical stage of AD) or advanced dementia. Future prospective studies should attempt to segment the RNFL and macula to know which retinal layers are predominantly affected and should investigate Age Macular Disease-AD associations (by calculating amount of druse; measuring thickness of Bruch's membrane and auto-fluorescence of retina in AD cases, etc.) (Ohno-Matsui 2011). We think this is an interesting and promising research field in an unfortunately increasingly common dementing disorder in the elderly. Time will tell whether we are only measuring and comparing different parameters with the latest technologies or whether we are facing a new and accessible biomarker of disease.